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Metzker-Pinto T, Tran YTH, Buzzatto-Leite I, Lok L, Sampar JF, Carvalho HF, Del Monte-Nieto G, Alvares LE. The chicken embryo brings new insights into the evolutionary role of WFDC1 during amniote development. Dev Biol 2025; 521:96-107. [PMID: 39947419 DOI: 10.1016/j.ydbio.2025.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 02/05/2025] [Accepted: 02/08/2025] [Indexed: 02/19/2025]
Abstract
WFDC1 encodes an extracellular matrix protein involved in cell proliferation, migration, and epithelial-mesenchymal transition in disease conditions. Despite this, Wfdc1-null mice display no discernible malformations while cattle bearing a WFDC1 mutation present multiple ocular defects, leaving the role of WFDC1 during embryonic development unclear. To address this, we used the chicken embryo as a model to investigate WFDC1 developmental roles in amniotes. We performed a comparative expression analysis during chicken and mouse development, which revealed expression in ectodermal and mesodermal derivatives, with both conserved and species-specific domains. Conserved expression was observed in the eye, otic vesicle, central and peripheral nervous systems, and neural crest cells. Chicken-specific expression was identified in mesodermal structures, including the notochord, limbs and heart. However, even in the conserved sites like the eyes, WFDC1 localizes to different retinal layers, indicating potential divergence roles in retinal development and function across species. In contrast, WFDC1 expression in the limb buds is specific to chicken, encompassing the distal mesenchyme, interdigital membranes, and blastemas. Functional enrichment analysis links WFDC1 to limb patterning, morphogenesis, and Wnt signaling. The species-specific differences likely stem from evolutionary changes in gene regulation, supported by differences in proximal cis-regulatory elements of the WFDC1 loci between chicken and mouse. The complexity of WFDC1 expression in the chicken embryo, along with WFDC1 regulatory conservation within birds, indicates that this gene may play specific roles in avian development, possibly contributing to features specific to this lineage. Future studies using the chicken model will be valuable in further uncovering the specific roles of WFDC1.
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Affiliation(s)
- Thaís Metzker-Pinto
- Department of Biochemistry and Tissue Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Yen T H Tran
- Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia
| | - Igor Buzzatto-Leite
- Department of Biochemistry and Tissue Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Lloyd Lok
- Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia
| | - Jórdan F Sampar
- Department of Biochemistry and Tissue Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Hernandes F Carvalho
- Department of Structural and Functional Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Gonzalo Del Monte-Nieto
- Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia.
| | - Lúcia E Alvares
- Department of Biochemistry and Tissue Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil.
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2
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Faraji N, Ebadpour N, Abavisani M, Gorji A. Unlocking Hope: Therapeutic Advances and Approaches in Modulating the Wnt Pathway for Neurodegenerative Diseases. Mol Neurobiol 2025; 62:3630-3652. [PMID: 39313658 PMCID: PMC11790780 DOI: 10.1007/s12035-024-04462-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 08/28/2024] [Indexed: 09/25/2024]
Abstract
Neurodegenerative diseases (NDs) are conditions characterized by sensory, motor, and cognitive impairments due to alterations in the structure and function of neurons in the central nervous system (CNS). Despite their widespread occurrence, the exact causes of NDs remain largely elusive, and existing treatments fall short in efficacy. The Wnt signaling pathway is an emerging molecular pathway that has been linked to the development and progression of various NDs. Wnt signaling governs numerous cellular processes, such as survival, polarity, proliferation, differentiation, migration, and fate specification, via a complex network of proteins. In the adult CNS, Wnt signaling regulates synaptic transmission, plasticity, memory formation, neurogenesis, neuroprotection, and neuroinflammation, all essential for maintaining neuronal function and integrity. Dysregulation of both canonical and non-canonical Wnt signaling pathways contributes to neurodegeneration through various mechanisms, such as amyloid-β accumulation, tau protein hyperphosphorylation, dopaminergic neuron degeneration, and synaptic dysfunction, prompting investigations into Wnt modulation as a therapeutic target to restore neuronal function and prevent or delay neurodegenerative processes. Modulating Wnt signaling has the potential to restore neuronal function and impede or postpone neurodegenerative processes, offering a therapeutic approach for targeting NDs. In this article, the current knowledge about how Wnt signaling works in Alzheimer's disease and Parkinson's disease is discussed. Our study aims to explore the molecular mechanisms, recent discoveries, and challenges involved in developing Wnt-based therapies.
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Affiliation(s)
- Navid Faraji
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negar Ebadpour
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Abavisani
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Gorji
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Epilepsy Research Center, Münster University, Münster, Germany.
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.
- Neurosurgery Department, Münster University, Münster, Germany.
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3
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Dey S, Ghosh M, Dev A. Signalling and molecular pathways, overexpressed receptors of colorectal cancer and effective therapeutic targeting using biogenic silver nanoparticles. Gene 2025; 936:149099. [PMID: 39557372 DOI: 10.1016/j.gene.2024.149099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 10/18/2024] [Accepted: 11/13/2024] [Indexed: 11/20/2024]
Abstract
Increasing morbidity and mortality in CRC is a potential threat to human health. The major challenges for better treatment outcomes are the heterogeneity of CRC cases, complicated molecular pathway cross-talks, the influence of gut dysbiosis in CRC, and the lack of multimodal target-specific drug delivery. The overexpression of many receptors in CRC cells may pave the path for targeting them with multiple ligands. The design of a more target-specific drug-delivery device with multiple ligand-functionalized, green-synthesized silver nanoparticles is highly promising and may also deliver other approved chemotherapeutic agents. This review presents the various aspects of colorectal cancer and over-expressed receptors that can be targeted with appropriate ligands to enhance the specific drug delivery potency of green synthesised silver nanoparticles. This review aims to broaden further research into this multi-ligand functionalised, safer and effective silver nano drug delivery system.
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Affiliation(s)
- Sandip Dey
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India
| | - Manik Ghosh
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India
| | - Abhimanyu Dev
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India.
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4
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Hong Z, Wang D, Qiao X, Xie Y, Yang S, Hao K, Han C, Liu H, Liu Z. Wnt5a negatively regulates melanogenesis in primary Arctic fox epidermal melanocytes. Gene 2025; 934:149045. [PMID: 39461575 DOI: 10.1016/j.gene.2024.149045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 09/16/2024] [Accepted: 10/22/2024] [Indexed: 10/29/2024]
Abstract
Melanocytes, which are mainly found in the epidermis, are responsible for the melanin of skin and hair, and thereby contribute to the appearance of skin and provide protection from damage by ultraviolet radiation. Our previous study revealed that the Wnt5a, one of the many genes that affect melanin production, might be involved in the coat color seasonal change of the Arctic fox by influencing skin melanogenesis. Although the role of Wnt5a in melanocyte lines and melanoma cells has been extensively studied, its role in primary epidermal melanocytes has not been explored. This study aimed to investigate the role and mechanism of the Wnt5a in influencing melanogenesis in Arctic fox primary epidermal melanocytes. We constructed the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) knockout plasmid targeting exons of the Wnt5a and transfected it into primary epidermal melanocytes. The results of the amplification knockout region assay, RT-qPCR assay, and western blot assay showed the success of Wnt5a knockout. RT-qPCR assay and melanin content assay showed that melanin production in melanocytes was significantly increased after Wnt5a knockout, and melanin-related key genes, such as microphthalmia-associated transcription factor, tyrosinase and tyrosinase-related protein 1, were significantly elevated. In addition, we also found that the expression of the β-catenin gene of the Wnt canonical pathway was significantly elevated after Wnt5a knockout. In conclusion, our results indicate that the Wnt5a plays a negative regulatory role in melanogenesis in primary epidermal melanocytes, and is presumably involved in antagonizing or inhibiting canonical Wnt signaling.
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Affiliation(s)
- Zhilin Hong
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Dongxian Wang
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Xian Qiao
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Yuchun Xie
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Shanshan Yang
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Kexing Hao
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Cong Han
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Huayun Liu
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China
| | - Zhengzhu Liu
- College of Animal Science and Technology, Hebei Normal University of Science & Technology, Hebei Key Laboratory of Special Animal Germplasm Resources Mining and Innovation, Qinhuangdao, Hebei 066004, China.
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5
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Alotaiq N, Khalifa AS, Youssef A, El-Nagar EG, Elwali NE, Habib HM, AlZaim I, Eid AH, Bakkar NMZ, El-Yazbi AF. Targeting GSK-3β for adipose dysfunction and cardiovascular complications of metabolic disease: An entangled WNT/β-catenin question. FASEB J 2024; 38:e70273. [PMID: 39726401 DOI: 10.1096/fj.202402470r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/10/2024] [Accepted: 12/17/2024] [Indexed: 12/28/2024]
Abstract
Individuals with metabolic syndrome have a high risk of developing cardiovascular disorders that is closely tied to visceral adipose tissue dysfunction, as well as an altered interaction between adipose tissue and the cardiovascular system. In metabolic syndrome, adipose tissue dysfunction is associated with increased hypertrophy, reduced vascularization, and hypoxia of adipocytes, leading to a pro-oxidative and pro-inflammatory environment. Among the pathways regulating adipose tissue homeostasis is the wingless-type mammary tumor virus integration site family (Wnt) signaling pathway, with both its canonical and non-canonical arms. Various modulators of the Wnt signaling have been identified to contribute to the development of metabolic diseases and their cardiovascular complications, with a particularly significant role played by Glycogen Synthase Kinase-3β (GSK-3β). GSK-3β levels and activities have various and often contrasting roles in obesity and related metabolic disorders, as well as their cardiovascular sequelae. Here, we explore the possibility that altered Wnt signaling and GSK-3β activities could serve as a connection between adipose tissue dysfunction and the development of cardiovascular disease in individuals with metabolic syndrome. We attempt to define a context-specific approach for intervention, which could possibly serve as a novel disease modifying therapy for the mitigation of such complications.
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Affiliation(s)
- Nasser Alotaiq
- Health Sciences Research Center, Imam Muhammad Ibn Saud Islamic University (IMISIU), Riyadh, Kingdom of Saudi Arabia
| | - Ahmed S Khalifa
- Faculty of Pharmacy, Alamein International University, Alamein, Egypt
| | - Amr Youssef
- Faculty of Pharmacy, Alamein International University, Alamein, Egypt
| | - Esraa G El-Nagar
- Faculty of Pharmacy, Alamein International University, Alamein, Egypt
| | - Nasr Eldin Elwali
- Deanship of Scientific Research, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Kingdom of Saudi Arabia
| | - Hosam M Habib
- Research & Innovation Hub, Alamein International University, Alamein, Egypt
| | - Ibrahim AlZaim
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | | | - Ahmed F El-Yazbi
- Faculty of Pharmacy, Alamein International University, Alamein, Egypt
- Research & Innovation Hub, Alamein International University, Alamein, Egypt
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
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6
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Wu J, Chen T, Zhang M, Li X, Fu R, Xu J, Nüssler A, Gu C. Atorvastatin exerts a preventive effect against steroid-induced necrosis of the femoral head by modulating Wnt5a release. Arch Toxicol 2024; 98:3365-3380. [PMID: 38971901 DOI: 10.1007/s00204-024-03817-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 06/27/2024] [Indexed: 07/08/2024]
Abstract
Steroid-induced osteonecrosis of the femoral head (SONFH) is a prevalent form of osteonecrosis in young individuals. More efficacious clinical strategies must be used to prevent and treat this condition. One of the mechanisms through which SONFH operates is the disruption of normal differentiation in bone marrow adipocytes and osteoblasts due to prolonged and extensive use of glucocorticoids (GCs). In vitro, it was observed that atorvastatin (ATO) effectively suppressed the impact of dexamethasone (DEX) on bone marrow mesenchymal stem cells (BMSCs), specifically by augmenting their lipogenic differentiation while impeding their osteogenic differentiation. To investigate the underlying mechanisms further, we conducted transcriptome sequencing of BMSCs subjected to different treatments, leading to the identification of Wnt5a as a crucial gene regulated by ATO. The analyses showed that ATO exhibited the ability to enhance the expression of Wnt5a and modulate the MAPK pathway while regulating the Wnt canonical signaling pathway via the WNT5A/LRP5 pathway. Our experimental findings provide further evidence that the combined treatment of ATO and DEX effectively mitigates the effects of DEX, resulting in the upregulation of osteogenic genes (Runx2, Alpl, Tnfrsf11b, Ctnnb1, Col1a) and the downregulation of adipogenic genes (Pparg, Cebpb, Lpl), meanwhile leading to the upregulation of Wnt5a expression. So, this study offers valuable insights into the potential mechanism by which ATO can be utilized in the prevention of SONFH, thereby holding significant implications for the prevention and treatment of SONFH in clinical settings.
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Affiliation(s)
- Junfeng Wu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Tao Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Minghang Zhang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xing Li
- Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou, China
| | - Rongkun Fu
- Department of Zhengzhou University Clinical Medicine, Zhengzhou, China
| | - Jianzhong Xu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Andreas Nüssler
- Department of Traumatology, BG Trauma Center, University of Tübingen, Schnarrenbergstr. 95, 72076, Tübingen, Germany
| | - Chenxi Gu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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7
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Borges KS, Little DW, Magalhães TDA, Ribeiro C, Dumontet T, Lapensee C, Basham KJ, Seth A, Azova S, Guagliardo NA, Barrett PQ, Berber M, O'Connell AE, Turcu AF, Lerario AM, Mohan DR, Rainey W, Carlone DL, Hirschhorn JN, Salic A, Breault DT, Hammer GD. Non-canonical Wnt signaling triggered by WNT2B drives adrenal aldosterone production. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.23.609423. [PMID: 39229119 PMCID: PMC11370552 DOI: 10.1101/2024.08.23.609423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
The steroid hormone aldosterone, produced by the zona glomerulosa (zG) of the adrenal gland, is a master regulator of plasma electrolytes and blood pressure. While aldosterone control by the renin-angiotensin system is well understood, other key regulatory factors have remained elusive. Here, we replicated a prior association between a non-coding variant in WNT2B and an increased risk of primary aldosteronism, a prevalent and debilitating disease caused by excessive aldosterone production. We further show that in both mice and humans, WNT2B is expressed in the mesenchymal capsule surrounding the adrenal cortex, in close proximity to the zG. Global loss of Wnt2b in the mouse results in a dysmorphic and hypocellular zG, with impaired aldosterone production. Similarly, humans harboring WNT2B loss-of-function mutations develop a novel form of Familial Hyperreninemic Hypoaldosteronism, designated here as Type 4. Additionally, we demonstrate that WNT2B signals by activating the non-canonical Wnt/planar cell polarity pathway. Our findings identify WNT2B as a key regulator of zG function and aldosterone production with important clinical implications.
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Affiliation(s)
- Kleiton S Borges
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Donald W Little
- Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, 48109, USA
| | | | - Claudio Ribeiro
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Typhanie Dumontet
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Chris Lapensee
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Kaitlin J Basham
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA
| | - Aishwarya Seth
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge MA, 02142
| | - Svetlana Azova
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Nick A Guagliardo
- Department of Pharmacology, University of Virginia, Charlottesville, VA, 22908-0735, USA
| | - Paula Q Barrett
- Department of Pharmacology, University of Virginia, Charlottesville, VA, 22908-0735, USA
| | - Mesut Berber
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Amy E O'Connell
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
- Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Adina F Turcu
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Antonio Marcondes Lerario
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Dipika R Mohan
- Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, 48109, USA
- Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, USA
| | - William Rainey
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Diana L Carlone
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
| | - Joel N Hirschhorn
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge MA, 02142
| | - Adrian Salic
- Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA
| | - David T Breault
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge MA, 02142
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
| | - Gary D Hammer
- Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, 48109, USA
- Endocrine Oncology Program, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA
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Kim HY, Jang HJ, Muthamil S, Shin UC, Lyu JH, Kim SW, Go Y, Park SH, Lee HG, Park JH. Novel insights into regulators and functional modulators of adipogenesis. Biomed Pharmacother 2024; 177:117073. [PMID: 38981239 DOI: 10.1016/j.biopha.2024.117073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/27/2024] [Accepted: 06/29/2024] [Indexed: 07/11/2024] Open
Abstract
Adipogenesis is a process that differentiates new adipocytes from precursor cells and is tightly regulated by several factors, including many transcription factors and various post-translational modifications. Recently, new roles of adipogenesis have been suggested in various diseases. However, the molecular mechanisms and functional modulation of these adipogenic genes remain poorly understood. This review summarizes the regulatory factors and modulators of adipogenesis and discusses future research directions to identify novel mechanisms regulating adipogenesis and the effects of adipogenic regulators in pathological conditions. The master adipogenic transcriptional factors PPARγ and C/EBPα were identified along with other crucial regulatory factors such as SREBP, Kroxs, STAT5, Wnt, FOXO1, SWI/SNF, KLFs, and PARPs. These transcriptional factors regulate adipogenesis through specific mechanisms, depending on the adipogenic stage. However, further studies related to the in vivo role of newly discovered adipogenic regulators and their function in various diseases are needed to develop new potent therapeutic strategies for metabolic diseases and cancer.
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Affiliation(s)
- Hyun-Yong Kim
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea; New Drug Development Center, Osong Medical Innovation Foundation, 123, Osongsaengmyeong-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 28160, Republic of Korea.
| | - Hyun-Jun Jang
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea; Research Group of Personalized Diet, Korea Food Research Institute, Wanju-gun, Jeollabuk-do 55365, Republic of Korea.
| | - Subramanian Muthamil
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea.
| | - Ung Cheol Shin
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea.
| | - Ji-Hyo Lyu
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea.
| | - Seon-Wook Kim
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea.
| | - Younghoon Go
- Korean Medicine (KM)-application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea.
| | - Seong-Hoon Park
- Genetic and Epigenetic Toxicology Research Group, Korea Institute of Toxicology, Daejeon 34141, Republic of Korea.
| | - Hee Gu Lee
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
| | - Jun Hong Park
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju, Jeollanam-do 58245, Republic of Korea; University of Science & Technology (UST), KIOM campus, Korean Convergence Medicine Major, Daejeon 34054, Republic of Korea.
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9
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Wang H, Zhang L, Hu C, Li H, Jiang M. Wnt signaling and tumors (Review). Mol Clin Oncol 2024; 21:45. [PMID: 38798312 PMCID: PMC11117032 DOI: 10.3892/mco.2024.2743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/23/2024] [Indexed: 05/29/2024] Open
Abstract
Wnt signaling is a highly conserved evolutionary pathway that plays a key role in regulation of embryonic development, as well as tissue homeostasis and regeneration. Abnormalities in Wnt signaling are associated with tumorigenesis and development, leading to poor prognosis in patients with cancer. However, the pharmacological effects and mechanisms underlying Wnt signaling and its inhibition in cancer treatment remain unclear. In addition, potential side effects of inhibiting this process are not well understood. Therefore, the present review outlines the role of Wnt signaling in tumorigenesis, development, metastasis, cancer stem cells, radiotherapy resistance and tumor immunity. The present review further identifies inhibitors that target Wnt signaling to provide a potential novel direction for cancer treatment. This may facilitate early application of safe and effective drugs targeting Wnt signaling in clinical settings. An in-depth understanding of the mechanisms underlying inhibition of Wnt signaling may improve the prognosis of patients with cancer.
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Affiliation(s)
- Huaishi Wang
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
| | - Lihai Zhang
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
| | - Chao Hu
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
| | - Hui Li
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
| | - Mingyan Jiang
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
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10
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Doddihal V, Mann FG, Ross EJ, McKinney MC, Guerrero-Hernández C, Brewster CE, McKinney SA, Sánchez Alvarado A. A PAK family kinase and the Hippo/Yorkie pathway modulate WNT signaling to functionally integrate body axes during regeneration. Proc Natl Acad Sci U S A 2024; 121:e2321919121. [PMID: 38713625 PMCID: PMC11098123 DOI: 10.1073/pnas.2321919121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 04/03/2024] [Indexed: 05/09/2024] Open
Abstract
Successful regeneration of missing tissues requires seamless integration of positional information along the body axes. Planarians, which regenerate from almost any injury, use conserved, developmentally important signaling pathways to pattern the body axes. However, the molecular mechanisms which facilitate cross talk between these signaling pathways to integrate positional information remain poorly understood. Here, we report a p21-activated kinase (smed-pak1) which functionally integrates the anterior-posterior (AP) and the medio-lateral (ML) axes. pak1 inhibits WNT/β-catenin signaling along the AP axis and, functions synergistically with the β-catenin-independent WNT signaling of the ML axis. Furthermore, this functional integration is dependent on warts and merlin-the components of the Hippo/Yorkie (YKI) pathway. Hippo/YKI pathway is a critical regulator of body size in flies and mice, but our data suggest the pathway regulates body axes patterning in planarians. Our study provides a signaling network integrating positional information which can mediate coordinated growth and patterning during planarian regeneration.
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Affiliation(s)
- Viraj Doddihal
- Stowers Institute for Medical Research, Kansas City, MO64110
| | | | - Eric J. Ross
- Stowers Institute for Medical Research, Kansas City, MO64110
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11
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An F, Song J, Chang W, Zhang J, Gao P, Wang Y, Xiao Z, Yan C. Research Progress on the Mechanism of the SFRP-Mediated Wnt Signalling Pathway Involved in Bone Metabolism in Osteoporosis. Mol Biotechnol 2024; 66:975-990. [PMID: 38194214 DOI: 10.1007/s12033-023-01018-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 12/01/2023] [Indexed: 01/10/2024]
Abstract
Osteoporosis (OP) is a metabolic bone disease linked to an elevated fracture risk, primarily stemming from disruptions in bone metabolism. Present clinical treatments for OP merely alleviate symptoms. Hence, there exists a pressing need to identify novel targets for the clinical treatment of OP. Research indicates that the Wnt signalling pathway is modulated by serum-secreted frizzled-related protein 5 (SFRP5), potentially serving as a pivotal regulator in bone metabolism disorders. Moreover, studies confirm elevated SFRP5 expression in OP, with SFRP5 overexpression leading to the downregulation of Wnt and β-catenin proteins in the Wnt signalling pathway, as well as the expression of osteogenesis-related marker molecules such as RUNX2, ALP, and OPN. Conversely, the opposite has been reported when SFRP5 is knocked out, suggesting that SFRP5 may be a key factor involved in the regulation of bone metabolism via the Wnt signalling axis. However, the molecular mechanisms underlying the action of SFRP5-induced OP have yet to be comprehensively elucidated. This review focusses on the molecular structure and function of SFRP5 and the potential molecular mechanisms of the SFRP5-mediated Wnt signalling pathway involved in bone metabolism in OP, providing reasonable evidence for the targeted therapy of SFRP5 for the prevention and treatment of OP.
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Affiliation(s)
- Fangyu An
- Teaching Experiment Training Center, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, China
| | - Jiayi Song
- School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, China
| | - Weirong Chang
- School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, China
| | - Jie Zhang
- School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, China
| | - Peng Gao
- School of Basic Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, China
| | - Yujie Wang
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, China
| | - Zhipan Xiao
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, China
| | - Chunlu Yan
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu, China.
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12
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Wang L, Li J. Morphogenesis of fungiform papillae in developing miniature pigs. Heliyon 2024; 10:e24953. [PMID: 38314265 PMCID: PMC10837543 DOI: 10.1016/j.heliyon.2024.e24953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 01/16/2024] [Accepted: 01/17/2024] [Indexed: 02/06/2024] Open
Abstract
Objective Fungiform papillae contain taste buds and play a critical role in mastication and the gustatory system. In this study, we report a series of sequential observations of organogenesis of fungiform papillae in miniature pigs, as well as changes in the expression of BMP2, BMP4, Wnt5a, Sox2, and Notch1 signaling pathway components. Design In this study, we investigated the spatiotemporal expression patterns of BMP, Wnt, Sox2 and Notch in the fungiform papillae of miniature pigs at the bud stage (E40), cap stage (E50) and bell stage (E60). Pregnant miniature pigs were obtained, and the samples were processed for histological staining. Immunohistochemistry and real-time PCR were used to detect the mRNA and protein expression levels of BMP2, BMP4, Wnt5a, Sox2, and Notch1. Results At E40, fungiform papillae were present on the anterior two-thirds of the tongue in a specific array and pattern. The fungiform papillae were enlarged and basically developed at E50 and were largest at the earlier stage (E60). Most of the BMP2 was concentrated in the epithelial layer and the connective tissue core of the fungal papilloma and gradually accumulated from E40-E60. BMP-4 was weakly expressed in the fungiform papillae epithelia, but BMP-4-positive cells were also observed in the developing tongue muscle at E50 and E60. Wnt5a-positive cells were observed in the fungiform papillae epithelia and developing tongue muscle at all three time points. Sox2-positive cells were observed only in fungiform papillae epithelial cells, and Notch1-positive cells could not be detected. Conclusions This study provides primary data regarding the morphogenesis and expression of developmental signals in the fungiform papillae of miniature pigs, establishing a foundation for further research in both this model and humans.
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Affiliation(s)
- Lingxiao Wang
- Department of Dental Implant Center, Beijing Stomatological Hospital, Capital Medical University, Capital Medical University School of Stomatology, No. 4 Tian Tan Xi Li, Beijing, 100050, China
| | - Jun Li
- Department of Dental Implant Center, Beijing Stomatological Hospital, Capital Medical University, Capital Medical University School of Stomatology, No. 4 Tian Tan Xi Li, Beijing, 100050, China
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13
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Huang FY, Wong DKH, Mak LY, Cheung TT, Zhang SS, Chau HT, Hui RWH, Seto WK, Yuen MF. FAT4 loss initiates hepatocarcinogenesis through the switching of canonical to noncanonical WNT signaling pathways. Hepatol Commun 2023; 7:e0338. [PMID: 38055646 PMCID: PMC10984662 DOI: 10.1097/hc9.0000000000000338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 10/19/2023] [Indexed: 12/08/2023] Open
Abstract
BACKGROUND Mutation and downregulation of FAT atypical cadherin 4 (FAT4) are frequently detected in HCC, suggesting a tumor suppressor role of FAT4. However, the underlying molecular mechanism remains elusive. METHODS CRISPR-Cas9 system was used to knockout FAT4 (FAT4-KO) in a normal human hepatic cell line L02 to investigate the impact of FAT4 loss on the development of HCC. RNA-sequencing and xenograft mouse model were used to study gene expression and tumorigenesis, respectively. The mechanistic basis of FAT4 loss on hepatocarcinogenesis was elucidated using in vitro experiments. RESULTS We found that FAT4-KO disrupted cell-cell adhesion, induced epithelial-mesenchymal transition, and increased expression of extracellular matrix components. FAT4-KO is sufficient for tumor initiation in a xenograft mouse model. RNA-sequencing of FAT4-KO cells identified PAK6-mediated WNT/β-catenin signaling to promote tumor growth. Suppression of PAK6 led to β-catenin shuttling out of the nucleus for ubiquitin-dependent degradation and constrained tumor growth. Further, RNA-sequencing of amassed FAT4-KO cells identified activation of WNT5A and ROR2. The noncanonical WNT5A/ROR2 signaling has no effect on β-catenin and its target genes (CCND1 and c-Myc) expression. Instead, we observed downregulation of receptors for WNT/β-catenin signaling, suggesting the shifting of β-catenin-dependent to β-catenin-independent pathways as tumor progression depends on its receptor expression. Both PAK6 and WNT5A could induce the expression of extracellular matrix glycoprotein, laminin subunit alpha 4. Laminin subunit alpha 4 upregulation in HCC correlated with poor patient survival. CONCLUSIONS Our data show that FAT4 loss is sufficient to drive HCC development through the switching of canonical to noncanonical Wingless-type signaling pathways. The findings may provide a mechanistic basis for an in-depth study of the two pathways in the early and late stages of HCC for precise treatment.
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Affiliation(s)
- Fung-Yu Huang
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR
| | - Danny Ka-Ho Wong
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR
| | - Tan-To Cheung
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR
- Department of Surgery, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR
| | - Sai-Sai Zhang
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR
| | - Hau-Tak Chau
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR
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14
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Lee KK, Changoor A, Grynpas MD, Mitchell J. Increased Osteoblast Gα S Promotes Ossification by Suppressing Cartilage and Enhancing Callus Mineralization During Fracture Repair in Mice. JBMR Plus 2023; 7:e10841. [PMID: 38130768 PMCID: PMC10731140 DOI: 10.1002/jbm4.10841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 10/16/2023] [Accepted: 10/19/2023] [Indexed: 12/23/2023] Open
Abstract
GαS, the stimulatory G protein α-subunit that raises intracellular cAMP levels by activating adenylyl cyclase, plays a vital role in bone development, maintenance, and remodeling. Previously, using transgenic mice overexpressing GαS in osteoblasts (GS-Tg), we demonstrated the influence of osteoblast GαS level on osteogenesis, bone turnover, and skeletal responses to hyperparathyroidism. To further investigate whether alterations in GαS levels affect endochondral bone repair, a postnatal bone regenerative process that recapitulates embryonic bone development, we performed stabilized tibial osteotomy in male GS-Tg mice at 8 weeks of age and examined the progression of fracture healing by micro-CT, histomorphometry, and gene expression analysis over a 4-week period. Bone fractures from GS-Tg mice exhibited diminished cartilage formation at the time of peak soft callus formation at 1 week post-fracture followed by significantly enhanced callus mineralization and new bone formation at 2 weeks post-fracture. The opposing effects on chondrogenesis and osteogenesis were validated by downregulation of chondrogenic markers and upregulation of osteogenic markers. Histomorphometric analysis at times of increased bone formation (2 and 3 weeks post-fracture) revealed excess fibroblast-like cells on newly formed woven bone surfaces and elevated osteocyte density in GS-Tg fractures. Coincident with enhanced callus mineralization and bone formation, GS-Tg mice showed elevated active β-catenin and Wntless proteins in osteoblasts at 2 weeks post-fracture, further substantiated by increased mRNA encoding various canonical Wnts and Wnt target genes, suggesting elevated osteoblastic Wnt secretion and Wnt/β-catenin signaling. The GS-Tg bony callus at 4 weeks post-fracture exhibited greater mineral density and decreased polar moment of inertia, resulting in improved material stiffness. These findings highlight that elevated GαS levels increase Wnt signaling, conferring an increased osteogenic differentiation potential at the expense of chondrogenic differentiation, resulting in improved mechanical integrity. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Kathy K Lee
- Department of Pharmacology and ToxicologyUniversity of TorontoTorontoCanada
- Lunenfeld‐Tanenbaum Research InstituteMount Sinai HospitalTorontoCanada
| | - Adele Changoor
- Lunenfeld‐Tanenbaum Research InstituteMount Sinai HospitalTorontoCanada
- Department of SurgeryUniversity of TorontoTorontoCanada
- Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
| | - Marc D Grynpas
- Lunenfeld‐Tanenbaum Research InstituteMount Sinai HospitalTorontoCanada
- Department of SurgeryUniversity of TorontoTorontoCanada
| | - Jane Mitchell
- Department of Pharmacology and ToxicologyUniversity of TorontoTorontoCanada
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15
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Ye Y, Zhang J, Feng X, Chen C, Chang Y, Qiu G, Wu Z, Zhang TJ, Gao B, Wu N. Exploring the association between congenital vertebral malformations and neural tube defects. J Med Genet 2023; 60:1146-1152. [PMID: 37775263 DOI: 10.1136/jmg-2023-109501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 09/07/2023] [Indexed: 10/01/2023]
Abstract
Congenital vertebral malformations (CVMs) and neural tube defects (NTDs) are common birth defects affecting the spine and nervous system, respectively, due to defects in somitogenesis and neurulation. Somitogenesis and neurulation rely on factors secreted from neighbouring tissues and the integrity of the axial structure. Crucial signalling pathways like Wnt, Notch and planar cell polarity regulate somitogenesis and neurulation with significant crosstalk. While previous studies suggest an association between CVMs and NTDs, the exact mechanism underlying this relationship remains unclear. In this review, we explore embryonic development, signalling pathways and clinical phenotypes involved in the association between CVMs and NTDs. Moreover, we provide a summary of syndromes that exhibit occurrences of both CVMs and NTDs. We aim to provide insights into the potential mechanisms underlying the association between CVMs and NTDs, thereby facilitating clinical diagnosis and management of these anomalies.
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Affiliation(s)
- Yongyu Ye
- Department of Orthopedic Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Jianan Zhang
- Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Xin Feng
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Chong Chen
- Department of Orthopedic Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Yunbing Chang
- Department of Orthopedic Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Guixing Qiu
- Department of Orthopedic Surgery, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
| | - Zhihong Wu
- Department of Orthopedic Surgery, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
| | - Terry Jianguo Zhang
- Department of Orthopedic Surgery, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
| | - Bo Gao
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- Centre for Translational Stem Cell Biology, Hong Kong, China
| | - Nan Wu
- Department of Orthopedic Surgery, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
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16
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Stevenson MJ, Phanor SK, Patel U, Gisselbrecht SS, Bulyk ML, O'Brien LL. Altered binding affinity of SIX1-Q177R correlates with enhanced WNT5A and WNT pathway effector expression in Wilms tumor. Dis Model Mech 2023; 16:dmm050208. [PMID: 37815464 PMCID: PMC10668032 DOI: 10.1242/dmm.050208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 09/27/2023] [Indexed: 10/11/2023] Open
Abstract
Wilms tumors present as an amalgam of varying proportions of tissues located within the developing kidney, one being the nephrogenic blastema comprising multipotent nephron progenitor cells (NPCs). The recurring missense mutation Q177R in NPC transcription factors SIX1 and SIX2 is most correlated with tumors of blastemal histology and is significantly associated with relapse. Yet, the transcriptional regulatory consequences of SIX1/2-Q177R that might promote tumor progression and recurrence have not been investigated extensively. Utilizing multiple Wilms tumor transcriptomic datasets, we identified upregulation of the gene encoding non-canonical WNT ligand WNT5A in addition to other WNT pathway effectors in SIX1/2-Q177R mutant tumors. SIX1 ChIP-seq datasets from Wilms tumors revealed shared binding sites for SIX1/SIX1-Q177R within a promoter of WNT5A and at putative distal cis-regulatory elements (CREs). We demonstrate colocalization of SIX1 and WNT5A in Wilms tumor tissue and utilize in vitro assays that support SIX1 and SIX1-Q177R activation of expression from the WNT5A CREs, as well as enhanced binding affinity within the WNT5A promoter that may promote the differential expression of WNT5A and other WNT pathway effectors associated with SIX1-Q177R tumors.
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Affiliation(s)
- Matthew J. Stevenson
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Sabrina K. Phanor
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Urvi Patel
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Stephen S. Gisselbrecht
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Martha L. Bulyk
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Lori L. O'Brien
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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17
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Wang W, Ma L, Zhao Y, Liu M, Ye W, Li X. Research progress on the role of the Wnt signaling pathway in pituitary adenoma. Front Endocrinol (Lausanne) 2023; 14:1216817. [PMID: 37780610 PMCID: PMC10538627 DOI: 10.3389/fendo.2023.1216817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 08/28/2023] [Indexed: 10/03/2023] Open
Abstract
Pituitary adenoma (PA) is the third most common central nervous system tumor originating from the anterior pituitary, but its pathogenesis remains unclear. The Wnt signaling pathway is a conserved pathway involved in cell proliferation, Self-renewal of stem cells, and cell differentiation. It is related to the occurrence of various tumors, including PA. This article reviews the latest developments in Wnt pathway inhibitors and pathway-targeted drugs. It discusses the possibility of combining Wnt pathway inhibitors with immunotherapy to provide a theoretical basis for the combined treatment of PA.
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Affiliation(s)
| | | | | | | | | | - Xianfeng Li
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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18
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Gelineau-van Waes J, van Waes MA, Hallgren J, Hulen J, Bredehoeft M, Ashley-Koch AE, Krupp D, Gregory SG, Stessman HA. Gene-nutrient interactions that impact magnesium homeostasis increase risk for neural tube defects in mice exposed to dolutegravir. Front Cell Dev Biol 2023; 11:1175917. [PMID: 37377737 PMCID: PMC10292217 DOI: 10.3389/fcell.2023.1175917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 05/19/2023] [Indexed: 06/29/2023] Open
Abstract
In 2018, data from a surveillance study in Botswana evaluating adverse birth outcomes raised concerns that women on antiretroviral therapy (ART) containing dolutegravir (DTG) may be at increased risk for neural tube defects (NTDs). The mechanism of action for DTG involves chelation of Mg2+ ions in the active site of the viral integrase. Plasma Mg2+ homeostasis is maintained primarily through dietary intake and reabsorption in the kidneys. Inadequate dietary Mg2+ intake over several months results in slow depletion of plasma Mg2+ and chronic latent hypomagnesemia, a condition prevalent in women of reproductive age worldwide. Mg2+ is critical for normal embryonic development and neural tube closure. We hypothesized that DTG therapy might slowly deplete plasma Mg2+ and reduce the amount available to the embryo, and that mice with pre-existing hypomagnesemia due to genetic variation and/or dietary Mg2+ insufficiency at the time of conception and initiation of DTG treatment would be at increased risk for NTDs. We used two different approaches to test our hypothesis: 1) we selected mouse strains that had inherently different basal plasma Mg2+ levels and 2) placed mice on diets with different concentrations of Mg2+. Plasma and urine Mg2+ were determined prior to timed mating. Pregnant mice were treated daily with vehicle or DTG beginning on the day of conception and embryos examined for NTDs on gestational day 9.5. Plasma DTG was measured for pharmacokinetic analysis. Our results demonstrate that hypomagnesemia prior to conception, due to genetic variation and/or insufficient dietary Mg2+ intake, increases the risk for NTDs in mice exposed to DTG. We also analyzed whole-exome sequencing data from inbred mouse strains and identified 9 predicted deleterious missense variants in Fam111a that were unique to the LM/Bc strain. Human FAM111A variants are associated with hypomagnesemia and renal Mg2+ wasting. The LM/Bc strain exhibits this same phenotype and was the strain most susceptible to DTG-NTDs. Our results suggest that monitoring plasma Mg2+ levels in patients on ART regimens that include DTG, identifying other risk factors that impact Mg2+ homeostasis, and correcting deficiencies in this micronutrient might provide an effective strategy for mitigating NTD risk.
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Affiliation(s)
- J. Gelineau-van Waes
- Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE, United States
| | | | - J. Hallgren
- Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE, United States
| | - J. Hulen
- Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE, United States
| | - M. Bredehoeft
- Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE, United States
| | - A. E. Ashley-Koch
- Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, United States
| | - D. Krupp
- Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - S. G. Gregory
- Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
| | - H. A. Stessman
- Department of Pharmacology and Neuroscience, School of Medicine, Creighton University, Omaha, NE, United States
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19
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Zhang J, Du L, Davis B, Gu Z, Lyu J, Zhao Z, Xu J, Morrison SJ. Osteolectin increases bone elongation and body length by promoting growth plate chondrocyte proliferation. Proc Natl Acad Sci U S A 2023; 120:e2220159120. [PMID: 37216542 PMCID: PMC10235998 DOI: 10.1073/pnas.2220159120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 04/21/2023] [Indexed: 05/24/2023] Open
Abstract
Osteolectin is a recently identified osteogenic growth factor that binds to Integrin α11 (encoded by Itga11), promoting Wnt pathway activation and osteogenic differentiation by bone marrow stromal cells. While Osteolectin and Itga11 are not required for the formation of the skeleton during fetal development, they are required for the maintenance of adult bone mass. Genome-wide association studies in humans reported a single-nucleotide variant (rs182722517) 16 kb downstream of Osteolectin associated with reduced height and plasma Osteolectin levels. In this study, we tested whether Osteolectin promotes bone elongation and found that Osteolectin-deficient mice have shorter bones than those of sex-matched littermate controls. Integrin α11 deficiency in limb mesenchymal progenitors or chondrocytes reduced growth plate chondrocyte proliferation and bone elongation. Recombinant Osteolectin injections increased femur length in juvenile mice. Human bone marrow stromal cells edited to contain the rs182722517 variant produced less Osteolectin and underwent less osteogenic differentiation than that of control cells. These studies identify Osteolectin/Integrin α11 as a regulator of bone elongation and body length in mice and humans.
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Affiliation(s)
- Jingzhu Zhang
- Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX75390
| | - Liming Du
- Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX75390
| | - Bethany Davis
- Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX75390
| | - Zhimin Gu
- Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX75390
| | - Junhua Lyu
- Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX75390
| | - Zhiyu Zhao
- Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX75390
| | - Jian Xu
- Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX75390
| | - Sean J. Morrison
- Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX75390
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX75390
- HHMI, University of Texas Southwestern Medical Center, Dallas, TX75390
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20
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Zhang Y, Li X, Gong Y, Du D, Chen H, Liu L, Cheng Z. Aberrant expression of UBE2C in endometrial cancer and its correlation to epithelial mesenchymal transition. Medicine (Baltimore) 2023; 102:e33834. [PMID: 37335710 DOI: 10.1097/md.0000000000033834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/21/2023] Open
Abstract
Ubiquitin-conjugating enzyme E2C (UBE2C), its overexpression promotes tumor progression, is a key component of the ubiquitin conjugating proteasome complex. Epithelial-mesenchymal transition, which is lost epithelial features and gained mesenchymal features in some epithelial cancers, is involved in epithelial cancers' invasiveness and metastasis. The aim of this study is to detect the expression of UBE2C, WNT5α, and E-cad in endometrial cancer (EC) and their clinical significance. The expression of UBE2C, WNT5α, and ZEB1 in 125 cases EC tissues were detected by immunohistochemistry. Patients clinicopathological, demography, and follow-up data were also collected. Positive rates of expression of UBE2C and ZEB1 were significantly higher in EC tissues when compared with the control tissues. The positive expression of UBE2C and ZEB1 were positively associated with tumor stages, local lymph node metastasis, and International Federation of Gynecology and Obstetrics (FIGO) stages. The positive rate of expression of WNT5a was significantly lower in EC tissues when compared with the control tissues. And positive expression of E-cad was inversely related to tumor stages, lymph node metastasis stages, and FIGO stages. Kaplan-Meier analyses demonstrated that positive expression of UBE2C or ZEB1 for EC patients had unfavorably overall survival time when compared with patients with negative expression of UBE2C or ZEB1. And EC patients with positive expression of WNT5a had favorably overall survival time when compared with EC patients with negative expression of WNT5a. Multivariate analysis demonstrated that positive expression UBE2C, WNT5α, and ZEB1, as well as FIGO stages were independent prognostic factors for EC patients. UBE2C, ZEB1, and WNT5a should be considered promising biomarkers for EC patients' prognosis.
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Affiliation(s)
- Yan Zhang
- Department of Gynaecology and Obstetrics, Bengbu City, China
| | - Xueting Li
- Department of Gynaecology and Obstetrics, Bengbu City, China
| | - Yingying Gong
- Department of Gynaecology and Obstetrics, Bengbu City, China
| | - Danli Du
- Department of Gynaecology and Obstetrics, Bengbu City, China
| | - Huilei Chen
- Department of Gynaecology and Obstetrics, Bengbu City, China
| | - Lei Liu
- Department of Gynaecology and Obstetrics, Bengbu City, China
| | - Zenong Cheng
- Department of Pathology, the First Affiliated Hospital of Bengbu Medical University, Bengbu City, China
- Department of Pathology, Bengbu Medical University, Bengbu City, China
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21
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Gill AK, McCormick PJ, Sochart D, Nalesso G. Wnt signalling in the articular cartilage: A matter of balance. Int J Exp Pathol 2023; 104:56-63. [PMID: 36843204 PMCID: PMC10009303 DOI: 10.1111/iep.12472] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 01/30/2023] [Accepted: 02/04/2023] [Indexed: 02/28/2023] Open
Abstract
Degradation of the articular cartilage is a hallmark of osteoarthritis, a progressive and chronic musculoskeletal condition, affecting millions of people worldwide. The activation of several signalling cascades is altered during disease development: among them, the Wnt signalling plays a pivotal role in the maintenance of tissue homeostasis. Increasing evidence is showing that its activation needs to be maintained within a certain range to avoid the triggering of degenerative mechanisms. In this review, we summarise our current knowledge about how a balanced activation of the Wnt signalling is maintained in the articular cartilage, with a particular focus on receptor-mediated mechanisms.
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Affiliation(s)
- Amandeep Kaur Gill
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary, University of London, London, UK
| | - Peter J McCormick
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary, University of London, London, UK
| | - David Sochart
- South West London Elective Orthopaedic Centre, Epsom, UK
| | - Giovanna Nalesso
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, University of Surrey, Guildford, UK
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22
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Sibuea S, Ho JK, Pouton CW, Haynes JM. TGFβ3, dibutyryl cAMP and a notch inhibitor modulate phenotype late in stem cell-derived dopaminergic neuron maturation. Front Cell Dev Biol 2023; 11:1111705. [PMID: 36819101 PMCID: PMC9928866 DOI: 10.3389/fcell.2023.1111705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/19/2023] [Indexed: 02/04/2023] Open
Abstract
The generation of midbrain dopaminergic neurons (mDAs) from pluripotent stem cells (hPSC) holds much promise for both disease modelling studies and as a cell therapy for Parkinson's disease (PD). Generally, dopaminergic neuron differentiation paradigms rely on inhibition of smad signalling for neural induction followed by hedgehog signalling and an elevation of β-catenin to drive dopaminergic differentiation. Post-patterning, differentiating dopaminergic neuron cultures are permitted time for maturation after which the success of these differentiation paradigms is usually defined by expression of tyrosine hydroxylase (TH), the rate limiting enzyme in the synthesis of dopamine. However, during maturation, culture media is often supplemented with additives to promote neuron survival and or promote cell differentiation. These additives include dibutyryl cyclic adenosine monophosphate (dbcAMP), transforming growth factor β3 (TGFβ3) and or the γ-secretase inhibitor (DAPT). While these factors are routinely added to cultures, their impact upon pluripotent stem cell-derived mDA phenotype is largely unclear. In this study, we differentiate pluripotent stem cells toward a dopaminergic phenotype and investigate how the omission of dbcAMP, TGFβ3 or DAPT, late in maturation, affects the regulation of multiple dopaminergic neuron phenotype markers. We now show that the removal of dbcAMP or TGFβ3 significantly and distinctly impacts multiple markers of the mDA phenotype (FOXA2, EN1, EN2, FOXA2, SOX6), while commonly increasing both MSX2 and NEUROD1 and reducing expression of both tyrosine hydroxylase and WNT5A. Removing DAPT significantly impacted MSX2, OTX2, EN1, and KCNJ6. In the absence of any stressful stimuli, we suggest that these culture additives should be viewed as mDA phenotype-modifying, rather than neuroprotective. We also suggest that their addition to cultures is likely to confound the interpretation of both transplantation and disease modelling studies.
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Affiliation(s)
- Shanti Sibuea
- Stem Cell Biology Group, Monash Institute of Pharmaceutical Sciences Monash University, Parkville, VIC, Australia,National Agency of Drug and Food Control, Jakarta, Indonesia
| | - Joan K. Ho
- Stem Cell Biology Group, Monash Institute of Pharmaceutical Sciences Monash University, Parkville, VIC, Australia
| | - Colin W. Pouton
- Stem Cell Biology Group, Monash Institute of Pharmaceutical Sciences Monash University, Parkville, VIC, Australia
| | - John M. Haynes
- Stem Cell Biology Group, Monash Institute of Pharmaceutical Sciences Monash University, Parkville, VIC, Australia,*Correspondence: John M. Haynes,
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23
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Cancer-Associated Adipocytes and Breast Cancer: Intertwining in the Tumor Microenvironment and Challenges for Cancer Therapy. Cancers (Basel) 2023; 15:cancers15030726. [PMID: 36765683 PMCID: PMC9913307 DOI: 10.3390/cancers15030726] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/15/2023] [Accepted: 01/16/2023] [Indexed: 01/26/2023] Open
Abstract
Adipocytes are the main components in breast tissue, and cancer-associated adipocytes (CAAs) are one of the most important components in the tumor microenvironment of breast cancer (BC). Bidirectional regulation was found between CAAs and BC cells. BC facilitates the dedifferentiation of adjacent adipocytes to form CAAs with morphological and biological changes. CAAs increase the secretion of multiple cytokines and adipokines to promote the tumorigenesis, progression, and metastasis of BC by remodeling the extracellular matrix, changing aromatase expression, and metabolic reprogramming, and shaping the tumor immune microenvironment. CAAs are also associated with the therapeutic response of BC and provide potential targets in BC therapy. The present review provides a comprehensive description of the crosstalk between CAAs and BC and discusses the potential strategies to target CAAs to overcome BC treatment resistance.
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24
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Yoon J, Sun J, Lee M, Hwang YS, Daar IO. Wnt4 and ephrinB2 instruct apical constriction via Dishevelled and non-canonical signaling. Nat Commun 2023; 14:337. [PMID: 36670115 PMCID: PMC9860048 DOI: 10.1038/s41467-023-35991-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 01/11/2023] [Indexed: 01/22/2023] Open
Abstract
Apical constriction is a cell shape change critical to vertebrate neural tube closure, and the contractile force required for this process is generated by actin-myosin networks. The signaling cue that instructs this process has remained elusive. Here, we identify Wnt4 and the transmembrane ephrinB2 protein as playing an instructive role in neural tube closure as members of a signaling complex we termed WERDS (Wnt4, EphrinB2, Ror2, Dishevelled (Dsh2), and Shroom3). Disruption of function or interaction among members of the WERDS complex results in defects of apical constriction and neural tube closure. The mechanism of action involves an interaction of ephrinB2 with the Dsh2 scaffold protein that enhances the formation of the WERDS complex, which in turn, activates Rho-associated kinase to induce apical constriction. Moreover, the ephrinB2/Dsh2 interaction promotes non-canonical Wnt signaling and shows how cross-talk between two major signal transduction pathways, Eph/ephrin and Wnt, coordinate morphogenesis of the neural tube.
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Affiliation(s)
- Jaeho Yoon
- Cancer & Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
| | - Jian Sun
- Cancer & Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA
| | - Moonsup Lee
- Cancer & Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA
| | - Yoo-Seok Hwang
- Cancer & Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA
| | - Ira O Daar
- Cancer & Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.
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25
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Dong CX, Malecki C, Robertson E, Hambly B, Jeremy R. Molecular Mechanisms in Genetic Aortopathy-Signaling Pathways and Potential Interventions. Int J Mol Sci 2023; 24:ijms24021795. [PMID: 36675309 PMCID: PMC9865322 DOI: 10.3390/ijms24021795] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/02/2023] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
Thoracic aortic disease affects people of all ages and the majority of those aged <60 years have an underlying genetic cause. There is presently no effective medical therapy for thoracic aneurysm and surgery remains the principal intervention. Unlike abdominal aortic aneurysm, for which the inflammatory/atherosclerotic pathogenesis is well established, the mechanism of thoracic aneurysm is less understood. This paper examines the key cell signaling systems responsible for the growth and development of the aorta, homeostasis of endothelial and vascular smooth muscle cells and interactions between pathways. The evidence supporting a role for individual signaling pathways in pathogenesis of thoracic aortic aneurysm is examined and potential novel therapeutic approaches are reviewed. Several key signaling pathways, notably TGF-β, WNT, NOTCH, PI3K/AKT and ANGII contribute to growth, proliferation, cell phenotype and survival for both vascular smooth muscle and endothelial cells. There is crosstalk between pathways, and between vascular smooth muscle and endothelial cells, with both synergistic and antagonistic interactions. A common feature of the activation of each is response to injury or abnormal cell stress. Considerable experimental evidence supports a contribution of each of these pathways to aneurysm formation. Although human information is less, there is sufficient data to implicate each pathway in the pathogenesis of human thoracic aneurysm. As some pathways i.e., WNT and NOTCH, play key roles in tissue growth and organogenesis in early life, it is possible that dysregulation of these pathways results in an abnormal aortic architecture even in infancy, thereby setting the stage for aneurysm development in later life. Given the fine tuning of these signaling systems, functional polymorphisms in key signaling elements may set up a future risk of thoracic aneurysm. Multiple novel therapeutic agents have been developed, targeting cell signaling pathways, predominantly in cancer medicine. Future investigations addressing cell specific targeting, reduced toxicity and also less intense treatment effects may hold promise for effective new medical treatments of thoracic aortic aneurysm.
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Affiliation(s)
- Charlotte Xue Dong
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
| | - Cassandra Malecki
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
- The Baird Institute, Camperdown, NSW 2042, Australia
| | - Elizabeth Robertson
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
| | - Brett Hambly
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
| | - Richmond Jeremy
- Faculty of Health and Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
- The Baird Institute, Camperdown, NSW 2042, Australia
- Correspondence:
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26
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Tigue ML, Loberg MA, Goettel JA, Weiss WA, Lee E, Weiss VL. Wnt Signaling in the Phenotype and Function of Tumor-Associated Macrophages. Cancer Res 2023; 83:3-11. [PMID: 36214645 PMCID: PMC9812914 DOI: 10.1158/0008-5472.can-22-1403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 08/26/2022] [Accepted: 10/05/2022] [Indexed: 02/03/2023]
Abstract
Tumor-associated macrophages (TAM) play an important role in supporting tumor growth and suppressing antitumor immune responses, and TAM infiltration has been associated with poor patient prognosis in various cancers. TAMs can be classified as pro-inflammatory, M1-like, or anti-inflammatory, M2-like. While multiple factors within the tumor microenvironment affect the recruitment, polarization, and functions of TAMs, accumulating evidence suggests that Wnt signaling represents an important, targetable driver of an immunosuppressive, M2-like TAM phenotype. TAM production of Wnt ligands mediates TAM-tumor cross-talk to support cancer cell proliferation, invasion, and metastasis. Targeting TAM polarization and the protumorigenic functions of TAMs through inhibitors of Wnt signaling may prove a beneficial treatment strategy in cancers where macrophages are prevalent in the microenvironment.
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Affiliation(s)
- Megan L Tigue
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Matthew A Loberg
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jeremy A Goettel
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - William A Weiss
- Departments of Neurology, Pediatrics, Neurosurgery, Brain Tumor Research Center, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California
| | - Ethan Lee
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
| | - Vivian L Weiss
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
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27
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Macyczko JR, Wang N, Zhao J, Ren Y, Lu W, Ikezu TC, Zhao N, Liu CC, Bu G, Li Y. Suppression of Wnt/β-Catenin Signaling Is Associated with Downregulation of Wnt1, PORCN, and Rspo2 in Alzheimer's Disease. Mol Neurobiol 2023; 60:26-35. [PMID: 36215026 PMCID: PMC9795414 DOI: 10.1007/s12035-022-03065-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 10/03/2022] [Indexed: 12/30/2022]
Abstract
Wnt and R-spondin (Rspo) proteins are two major types of endogenous Wnt/β-catenin signaling agonists. While Wnt/β-catenin signaling is greatly diminished in Alzheimer's disease (AD), it remains to be elucidated whether the inhibition of this pathway is associated with dysregulation of Wnt and Rspo proteins. By analyzing temporal cortex RNA-seq data of the human postmortem brain samples, we found that WNT1 and RRPO2 were significantly downregulated in human AD brains. In addition, the expression of Wnt acyltransferase porcupine (PORCN), which is essential for Wnt maturation and secretion, was greatly deceased in these human AD brains. Interestingly, the lowest levels of WNT1, PORCN, and RSPO2 expression were found in human AD brains carrying two copies of APOE4 allele, the strongest genetic risk factor of late-onset AD. Importantly, there were positive correlations among the levels of WNT1, PORCN, and RSPO2 expression in human AD brains. Supporting observations in humans, Wnt1, PORCN, and Rspo2 were downregulated and Wnt/β-catenin signaling was diminished in the 5xFAD amyloid model mice. In human APOE-targeted replacement mice, downregulation of WNT1, PORCN, and RSPO2 expression was positively associated with aging and APOE4 genotype. Finally, WNT1 and PORCN expression and Wnt/β-catenin signaling were inhibited in human APOE4 iPSC-derived astrocytes when compared to the isogenic APOE3 iPSC-derived astrocytes. Altogether, our findings suggest that the dysregulations of Wnt1, PORCN, and Rspo2 could be coordinated together to diminish Wnt/β-catenin signaling in aging- and APOE4-dependent manners in the AD brain.
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Affiliation(s)
- Jesse R Macyczko
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Na Wang
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Jing Zhao
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
- Center for Regenerative Medicine, Neuroregeneration Laboratory, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Yingxue Ren
- Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Wenyan Lu
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
- Center for Regenerative Medicine, Neuroregeneration Laboratory, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Tadafumi C Ikezu
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Na Zhao
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Chia-Chen Liu
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Guojun Bu
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA
- Center for Regenerative Medicine, Neuroregeneration Laboratory, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Yonghe Li
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
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28
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Duarte-Olivenza C, Hurle JM, Montero JA, Lorda-Diez CI. Modeling the Differentiation of Embryonic Limb Chondroprogenitors by Cell Death and Cell Senescence in High Density Micromass Cultures and Their Regulation by FGF Signaling. Cells 2022; 12:cells12010175. [PMID: 36611968 PMCID: PMC9818968 DOI: 10.3390/cells12010175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/20/2022] [Accepted: 12/28/2022] [Indexed: 01/04/2023] Open
Abstract
Considering the importance of programmed cell death in the formation of the skeleton during embryonic development, the aim of the present study was to analyze whether regulated cell degeneration also accompanies the differentiation of embryonic limb skeletal progenitors in high-density tridimensional cultures (micromass cultures). Our results show that the formation of primary cartilage nodules in the micromass culture assay involves a patterned process of cell death and cell senescence, complementary to the pattern of chondrogenesis. As occurs in vivo, the degenerative events were preceded by DNA damage detectable by γH2AX immunolabeling and proceeded via apoptosis and cell senescence. Combined treatments of the cultures with growth factors active during limb skeletogenesis, including FGF, BMP, and WNT revealed that FGF signaling modulates the response of progenitors to signaling pathways implicated in cell death. Transcriptional changes induced by FGF treatments suggested that this function is mediated by the positive regulation of the genetic machinery responsible for apoptosis and cell senescence together with hypomethylation of the Sox9 gene promoter. We propose that FGF signaling exerts a primordial function in the embryonic limb conferring chondroprogenitors with their biological properties.
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Affiliation(s)
| | | | - Juan A. Montero
- Correspondence: (J.A.M.); (C.I.L.-D.); Fax: +34-942201923 (J.A.M. and C.I.L.-D.)
| | - Carlos I. Lorda-Diez
- Correspondence: (J.A.M.); (C.I.L.-D.); Fax: +34-942201923 (J.A.M. and C.I.L.-D.)
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29
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To β or Not to β: How Important Is β-Catenin Dependent and Independent WNT Signaling in CLL? Cancers (Basel) 2022; 15:cancers15010194. [PMID: 36612190 PMCID: PMC9818906 DOI: 10.3390/cancers15010194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/31/2022] Open
Abstract
WNT pathways play an important role in cancer development and progression, but WNT pathways can also inhibit growth in melanoma, prostate, and ovarian cancers. Chronic lymphocytic leukemia (CLL) is known for its overexpression of several WNT ligands and receptors. Canonical WNT signaling is β-catenin-dependent, whereas non-canonical WNT signaling is β-catenin-independent. Research on WNT in CLL focuses mainly on non-canonical signaling due to the high expression of the WNT-5a receptor ROR1. However, it was also shown that mutations in canonical WNT pathway genes can lead to WNT activation in CLL. The focus of this review is β-catenin-independent signaling and β-catenin-dependent signaling within CLL cells and the role of WNT in the leukemic microenvironment. The major role of WNT pathways in CLL pathogenesis also makes WNT a possible therapeutic target, directly or in combination with other drugs.
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30
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Zhang CH, Gao Y, Hung HH, Zhuo Z, Grodzinsky AJ, Lassar AB. Creb5 coordinates synovial joint formation with the genesis of articular cartilage. Nat Commun 2022; 13:7295. [PMID: 36435829 PMCID: PMC9701237 DOI: 10.1038/s41467-022-35010-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 11/15/2022] [Indexed: 11/28/2022] Open
Abstract
While prior work has established that articular cartilage arises from Prg4-expressing perichondrial cells, it is not clear how this process is specifically restricted to the perichondrium of synovial joints. We document that the transcription factor Creb5 is necessary to initiate the expression of signaling molecules that both direct the formation of synovial joints and guide perichondrial tissue to form articular cartilage instead of bone. Creb5 promotes the generation of articular chondrocytes from perichondrial precursors in part by inducing expression of signaling molecules that block a Wnt5a autoregulatory loop in the perichondrium. Postnatal deletion of Creb5 in the articular cartilage leads to loss of both flat superficial zone articular chondrocytes coupled with a loss of both Prg4 and Wif1 expression in the articular cartilage; and a non-cell autonomous up-regulation of Ctgf. Our findings indicate that Creb5 promotes joint formation and the subsequent development of articular chondrocytes by driving the expression of signaling molecules that both specify the joint interzone and simultaneously inhibit a Wnt5a positive-feedback loop in the perichondrium.
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Affiliation(s)
- Cheng-Hai Zhang
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute at Harvard Medical School, 240 Longwood Ave., Boston, MA, 02115, USA.
| | - Yao Gao
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute at Harvard Medical School, 240 Longwood Ave., Boston, MA, 02115, USA
| | - Han-Hwa Hung
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Zhu Zhuo
- Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Alan J Grodzinsky
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Andrew B Lassar
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute at Harvard Medical School, 240 Longwood Ave., Boston, MA, 02115, USA.
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31
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Flanagan DJ, Woodcock SA, Phillips C, Eagle C, Sansom OJ. Targeting ligand-dependent wnt pathway dysregulation in gastrointestinal cancers through porcupine inhibition. Pharmacol Ther 2022; 238:108179. [PMID: 35358569 PMCID: PMC9531712 DOI: 10.1016/j.pharmthera.2022.108179] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 12/20/2022]
Abstract
Gastrointestinal cancers are responsible for more cancer deaths than any other system of the body. This review summarises how Wnt pathway dysregulation contributes to the development of the most common gastrointestinal cancers, with a particular focus on the nature and frequency of upstream pathway aberrations. Tumors with upstream aberrations maintain a dependency on the presence of functional Wnt ligand, and are predicted to be tractable to inhibitors of Porcupine, an enzyme that plays a key role in Wnt secretion. We summarise available pre-clinical efficacy data from Porcupine inhibitors in vitro and in vivo, as well as potential toxicities and the data from early phase clinical trials. We appraise the rationale for biomarker-defined targeted approaches, as well as outlining future opportunities for combination with other therapeutics.
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Affiliation(s)
- Dustin J Flanagan
- Cancer Research UK Beatson Institute, Glasgow, UK; Biomedicine Discovery Institute, Monash University, Melbourne, Australia
| | | | | | | | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
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32
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Ragab N, Bauer J, Uhmann A, Marx A, Hahn H, Simon-Keller K. Tumor suppressive functions of WNT5A in rhabdomyosarcoma. Int J Oncol 2022; 61:102. [PMID: 35796028 PMCID: PMC9291248 DOI: 10.3892/ijo.2022.5392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 06/07/2022] [Indexed: 12/02/2022] Open
Abstract
Rhabdomyosarcoma (RMS) is a highly aggressive soft tissue malignancy that predominantly affects children. The main subtypes are alveolar RMS (ARMS) and embryonal RMS (ERMS) and the two show an impaired muscle differentiation phenotype. One pathway involved in muscle differentiation is WNT signaling. However, the role of this pathway in RMS is far from clear. Our recent data showed that the canonical WNT/β-Catenin pathway serves a subordinate role in RMS, whereas non-canonical WNT signaling probably is more important for this tumor entity. The present study investigated the role of WNT5A, which is the major ligand of non-canonical WNT signaling, in ERMS and ARMS. Gene expression analysis showed that WNT5A was expressed in human RMS samples and that its expression is more pronounced in ERMS. When stably overexpressed in RMS cell lines, WNT5A decreased proliferation and migration of the cells as demonstrated by BrdU incorporation and Transwell migration or scratch assay, respectively. WNT5A also decreased the self-renewal capacity and the expression of stem cell markers and modulates the levels of muscle differentiation markers as shown by sphere assay and western blot analysis, respectively. Finally, overexpression of WNT5A can destabilize active β-Catenin of RMS cells. A WNT5A knockdown has opposite effects. Together, the results suggest that WNT5A has tumor suppressive functions in RMS, which accompanies downregulation of β-Catenin.
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Affiliation(s)
- Nada Ragab
- Institute of Human Genetics, University Medical Center Göttingen, D‑37073 Göttingen, Germany
| | - Julia Bauer
- Institute of Human Genetics, University Medical Center Göttingen, D‑37073 Göttingen, Germany
| | - Anja Uhmann
- Institute of Human Genetics, University Medical Center Göttingen, D‑37073 Göttingen, Germany
| | - Alexander Marx
- Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, D‑68167 Mannheim, Germany
| | - Heidi Hahn
- Institute of Human Genetics, University Medical Center Göttingen, D‑37073 Göttingen, Germany
| | - Katja Simon-Keller
- Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, D‑68167 Mannheim, Germany
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33
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Vlashi R, Zhang X, Wu M, Chen G. Wnt signaling: essential roles in osteoblast differentiation, bone metabolism and therapeutic implications for bone and skeletal disorders. Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022] Open
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ROR2 regulates self-renewal and maintenance of hair follicle stem cells. Nat Commun 2022; 13:4449. [PMID: 35915068 PMCID: PMC9343661 DOI: 10.1038/s41467-022-32239-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 07/21/2022] [Indexed: 11/25/2022] Open
Abstract
Hair follicles undergo cycles of regeneration fueled by hair follicle stem cells (HFSCs). While β-catenin-dependent canonical Wnt signaling has been extensively studied and implicated in HFSC activation and fate determination, very little is known about the function of β-catenin-independent Wnt signaling in HFSCs. In this study, we investigate the functional role of ROR2, a Wnt receptor, in HFSCs. By analyzing Ror2-depleted HFSCs, we uncover that ROR2 is not only essential to regulate Wnt-activated signaling that is responsible for HFSC activation and self-renewal, but it is also required to maintain proper ATM/ATR-dependent DNA damage response, which is indispensable for the long-term maintenance of HFSCs. In analyzing HFSCs lacking β-catenin, we identify a compensatory role of ROR2-PKC signaling in protecting β-catenin-null HFSCs from the loss of stem cell pool. Collectively, our study unveils a previously unrecognized role of ROR2 in regulation of stem cell self-renewal and maintenance. Wnt signaling functions in tissue homeostasis and tumorigenesis. Here the authors show that ROR2, a Wnt receptor, plays roles not only in transducing Wnt signaling, but also in regulation of DNA damage response critical for stem cell maintenance.
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Montazer M, Taghehchian N, Mojarrad M, Moghbeli M. Role of microRNAs in regulation of WNT signaling pathway in urothelial and prostate cancers. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00315-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Urothelial cancer (UC) and prostate cancer (PCa) are the most common cancers among men with a high ratio of mortality in advanced-stages. The higher risk of these malignancies among men can be associated with higher carcinogens exposure. Molecular pathology of UC and PCa is related to the specific mutations and aberrations in some signaling pathways. WNT signaling is a highly regulated pathway that has a pivotal role during urothelial and prostate development and homeostasis. This pathway also plays a vital role in adult stem cell niches to maintain a balance between stemness and differentiation. Deregulation of the WNT pathway is frequently correlated with tumor progression and metastasis in urothelial and prostate tumors. Therefore, regulatory factors of WNT pathways are being investigated as diagnostic or prognostic markers and novel therapeutic targets during urothelial and prostate tumorigenesis. MicroRNAs (miRNAs) have a pivotal role in WNT signaling regulation in which there are interactions between miRNAs and WNT signaling pathway during tumor progression. Since, the miRNAs are sensitive, specific, and noninvasive, they can be introduced as efficient biomarkers of tumor progression.
Main body
In present review, we have summarized all of the miRNAs that have been involved in regulation of WNT signaling pathway in urothelial and prostate cancers.
Conclusions
It was observed that miRNAs were mainly involved in regulation of WNT signaling in bladder cancer cells through targeting the WNT ligands and cytoplasmic WNT components such as WNT5A, WNT7A, CTNNB1, GSK3β, and AXIN. Whereas, miRNAs were mainly involved in regulation of WNT signaling in prostate tumor cells via targeting the cytoplasmic WNT components and WNT related transcription factors such as CTNNB1, GSK3β, AXIN, TCF7, and LEF1. MiRNAs mainly functioned as tumor suppressors in bladder and prostate cancers through the WNT signaling inhibition. This review paves the way of introducing a noninvasive diagnostic panel of WNT related miRNAs in urothelial and prostate tumors.
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Lin Q, Wu L, Chatla S, Chowdhury FA, Atale N, Joseph J, Du W. Hematopoietic stem cell regeneration through paracrine regulation of the Wnt5a/Prox1 signaling axis. J Clin Invest 2022; 132:155914. [PMID: 35703178 PMCID: PMC9197516 DOI: 10.1172/jci155914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 05/05/2022] [Indexed: 11/20/2022] Open
Abstract
The crosstalk between the BM microenvironment (niche) and hematopoietic stem cells (HSCs) is critical for HSC regeneration. Here, we show that in mice, deletion of the Fanconi anemia (FA) genes Fanca and Fancc dampened HSC regeneration through direct effects on HSCs and indirect effects on BM niche cells. FA HSCs showed persistent upregulation of the Wnt target Prox1 in response to total body irradiation (TBI). Accordingly, lineage-specific deletion of Prox1 improved long-term repopulation of the irradiated FA HSCs. Forced expression of Prox1 in WT HSCs mimicked the defective repopulation phenotype of FA HSCs. WT mice but not FA mice showed significant induction by TBI of BM stromal Wnt5a protein. Mechanistically, FA proteins regulated stromal Wnt5a expression, possibly through modulating the Wnt5a transcription activator Pax2. Wnt5a treatment of irradiated FA mice enhanced HSC regeneration. Conversely, Wnt5a neutralization inhibited HSC regeneration after TBI. Wnt5a secreted by LepR+CXCL12+ BM stromal cells inhibited β-catenin accumulation, thereby repressing Prox1 transcription in irradiated HSCs. The detrimental effect of deregulated Wnt5a/Prox1 signaling on HSC regeneration was also observed in patients with FA and aged mice. Irradiation induced upregulation of Prox1 in the HSCs of aged mice, and deletion of Prox1 in aged HSCs improved HSC regeneration. Treatment of aged mice with Wnt5a enhanced hematopoietic repopulation. Collectively, these findings identified the paracrine Wnt5a/Prox1 signaling axis as a regulator of HSC regeneration under conditions of injury and aging.
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Affiliation(s)
- Qiqi Lin
- Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Limei Wu
- Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Srinivas Chatla
- Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Fabliha A Chowdhury
- Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Neha Atale
- Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Jonathan Joseph
- University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.,University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Wei Du
- Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
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Parada C, Banavar SP, Khalilian P, Rigaud S, Michaut A, Liu Y, Joshy DM, Campàs O, Gros J. Mechanical feedback defines organizing centers to drive digit emergence. Dev Cell 2022; 57:854-866.e6. [PMID: 35413235 DOI: 10.1016/j.devcel.2022.03.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 01/25/2022] [Accepted: 03/10/2022] [Indexed: 11/03/2022]
Abstract
During embryonic development, digits gradually emerge in a periodic pattern. Although genetic evidence indicates that digit formation results from a self-organizing process, the underlying mechanisms are still unclear. Here, we find that convergent-extension tissue flows driven by active stresses underlie digit formation. These active stresses simultaneously shape cartilage condensations and lead to the emergence of a compressive stress region that promotes high activin/p-SMAD/SOX9 expression, thereby defining digit-organizing centers via a mechanical feedback. In Wnt5a mutants, such mechanical feedback is disrupted due to the loss of active stresses, organizing centers do not emerge, and digit formation is precluded. Thus, digit emergence does not result solely from molecular interactions, as was previously thought, but requires a mechanical feedback that ensures continuous coupling between phalanx specification and elongation. Our work, which links mechanical and molecular signals, provides a mechanistic context for the emergence of organizing centers that may underlie various developmental processes.
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Affiliation(s)
- Carolina Parada
- Department of Developmental and Stem Cell Biology, Institut Pasteur, 75724 Paris Cedex 15, France; CNRS UMR 3738, 25 rue du Dr Roux, 75015 Paris, France
| | - Samhita P Banavar
- Department of Physics, University of California, Santa Barbara, CA 93106-5070, USA
| | - Parisa Khalilian
- Department of Developmental and Stem Cell Biology, Institut Pasteur, 75724 Paris Cedex 15, France; CNRS UMR 3738, 25 rue du Dr Roux, 75015 Paris, France
| | - Stephane Rigaud
- Image Analysis Hub, C2RT, Institut Pasteur, 75724 Paris Cedex 15, France
| | - Arthur Michaut
- Department of Developmental and Stem Cell Biology, Institut Pasteur, 75724 Paris Cedex 15, France; CNRS UMR 3738, 25 rue du Dr Roux, 75015 Paris, France
| | - Yucen Liu
- Department of Mechanical Engineering, University of California, Santa Barbara, CA 93106-5070, USA
| | - Dennis Manjaly Joshy
- Department of Mechanical Engineering, University of California, Santa Barbara, CA 93106-5070, USA
| | - Otger Campàs
- Department of Mechanical Engineering, University of California, Santa Barbara, CA 93106-5070, USA; Department of Molecular, Cell and Developmental Biology, University of California, Santa Barbara, CA, USA; Cluster of Excellence Physics of Life, TU Dresden, 01062 Dresden, Germany.
| | - Jerome Gros
- Department of Developmental and Stem Cell Biology, Institut Pasteur, 75724 Paris Cedex 15, France; CNRS UMR 3738, 25 rue du Dr Roux, 75015 Paris, France.
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38
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Chronopoulou E, Koika V, Tsiveriotis K, Stefanidis K, Kalogeropoulos S, Georgopoulos N, Adonakis G, Kaponis A. Wnt4, Wnt6 and β-catenin expression in human placental tissue - is there a link with first trimester miscarriage? Results from a pilot study. Reprod Biol Endocrinol 2022; 20:51. [PMID: 35300692 PMCID: PMC8928677 DOI: 10.1186/s12958-022-00923-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 03/03/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Demystifying the events around early pregnancy is challenging. A wide network of mediators and signaling cascades orchestrate the processes of implantation and trophoblast proliferation. Dysregulation of these pathways could be implicated in early pregnancy loss. There is accumulating evidence around the role of Wnt pathway in implantation and early pregnancy. The purpose of this study was to explore alterations in the expression of Wnt4, Wnt6 and β-catenin in placental tissue obtained from human first trimester euploid miscarriages versus normally developing early pregnancies. METHODS The study group consisted of first trimester miscarriages (early embryonic demises and incomplete miscarriages) and the control group of social terminations of pregnancy (TOPs). The placental mRNA expression of Wnt4, Wnt6 and β-catenin was studied using reverse transcription PCR and real time PCR. Only euploid conceptions were included in the analysis. RESULTS Wnt4 expression was significantly increased in placental tissue from first trimester miscarriages versus controls (p = 0.003). No significant difference was documented in the expression of Wnt6 (p = 0.286) and β-catenin (p = 0.793). There was a 5.1fold increase in Wnt4 expression for early embryonic demises versus TOPs and a 7.6fold increase for incomplete miscarriages versus TOPs - no significant difference between the two subgroups of miscarriage (p = 0.533). CONCLUSIONS This is, to our knowledge, the first study demonstrating significant alteration of Wnt4 expression in human placental tissue, from failed early pregnancies compared to normal controls. Undoubtedly, a more profound study is needed to confirm these preliminary findings and explore Wnt mediators as potential targets for strategies to predict and prevent miscarriage.
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Affiliation(s)
- Elpiniki Chronopoulou
- Department of Obstetrics and Gynaecology, University General Hospital of Patras, 265 04, Rion, Greece.
- Department of Obstetrics and Gynaecology, Division of Reproductive Endocrinology, University General Hospital of Patras, 265 04, Rion, Greece.
| | - Vasiliki Koika
- Department of Obstetrics and Gynaecology, Division of Reproductive Endocrinology, University General Hospital of Patras, 265 04, Rion, Greece
| | - Konstantinos Tsiveriotis
- Department of Obstetrics and Gynaecology, University General Hospital of Patras, 265 04, Rion, Greece
| | - Konstantinos Stefanidis
- Department of Obstetrics and Gynaecology, University Hospital of Athens, "Alexandra", Lourou 4-2, 115 28, Athens, Greece
| | - Sotirios Kalogeropoulos
- Department of Obstetrics and Gynaecology, University General Hospital of Patras, 265 04, Rion, Greece
| | - Neoklis Georgopoulos
- Department of Obstetrics and Gynaecology, Division of Reproductive Endocrinology, University General Hospital of Patras, 265 04, Rion, Greece
| | - George Adonakis
- Department of Obstetrics and Gynaecology, University General Hospital of Patras, 265 04, Rion, Greece
| | - Apostolos Kaponis
- Department of Obstetrics and Gynaecology, University General Hospital of Patras, 265 04, Rion, Greece
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Shah K, Kazi JU. Phosphorylation-Dependent Regulation of WNT/Beta-Catenin Signaling. Front Oncol 2022; 12:858782. [PMID: 35359365 PMCID: PMC8964056 DOI: 10.3389/fonc.2022.858782] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 02/16/2022] [Indexed: 01/11/2023] Open
Abstract
WNT/β-catenin signaling is a highly complex pathway that plays diverse roles in various cellular processes. While WNT ligands usually signal through their dedicated Frizzled receptors, the decision to signal in a β-catenin-dependent or -independent manner rests upon the type of co-receptors used. Canonical WNT signaling is β-catenin-dependent, whereas non-canonical WNT signaling is β-catenin-independent according to the classical definition. This still holds true, albeit with some added complexity, as both the pathways seem to cross-talk with intertwined networks that involve the use of different ligands, receptors, and co-receptors. β-catenin can be directly phosphorylated by various kinases governing its participation in either canonical or non-canonical pathways. Moreover, the co-activators that associate with β-catenin determine the output of the pathway in terms of induction of genes promoting proliferation or differentiation. In this review, we provide an overview of how protein phosphorylation controls WNT/β-catenin signaling, particularly in human cancer.
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Affiliation(s)
- Kinjal Shah
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Julhash U. Kazi
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden
- *Correspondence: Julhash U. Kazi,
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Maimets M, Pedersen MT, Guiu J, Dreier J, Thodberg M, Antoku Y, Schweiger PJ, Rib L, Bressan RB, Miao Y, Garcia KC, Sandelin A, Serup P, Jensen KB. Mesenchymal-epithelial crosstalk shapes intestinal regionalisation via Wnt and Shh signalling. Nat Commun 2022; 13:715. [PMID: 35132078 PMCID: PMC8821716 DOI: 10.1038/s41467-022-28369-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 01/14/2022] [Indexed: 12/13/2022] Open
Abstract
Organs are anatomically compartmentalised to cater for specialised functions. In the small intestine (SI), regionalisation enables sequential processing of food and nutrient absorption. While several studies indicate the critical importance of non-epithelial cells during development and homeostasis, the extent to which these cells contribute to regionalisation during morphogenesis remains unexplored. Here, we identify a mesenchymal-epithelial crosstalk that shapes the developing SI during late morphogenesis. We find that subepithelial mesenchymal cells are characterised by gradients of factors supporting Wnt signalling and stimulate epithelial growth in vitro. Such a gradient impacts epithelial gene expression and regional villus formation along the anterior-posterior axis of the SI. Notably, we further provide evidence that Wnt signalling directly regulates epithelial expression of Sonic Hedgehog (SHH), which, in turn, acts on mesenchymal cells to drive villi formation. Taken together our results uncover a mechanistic link between Wnt and Hedgehog signalling across different cellular compartments that is central for anterior-posterior regionalisation and correct formation of the SI. The small intestine forms via crosstalk between epithelial and mesenchymal cell compartments. Here, the authors show that a gradient of Wnt signalling along the anterior-posterior axis regulates Sonic Hedgehog which is required for correct formation and regionalization of the small intestine.
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41
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Škorić-Milosavljević D, Tadros R, Bosada FM, Tessadori F, van Weerd JH, Woudstra OI, Tjong FV, Lahrouchi N, Bajolle F, Cordell HJ, Agopian A, Blue GM, Barge-Schaapveld DQ, Gewillig M, Preuss C, Lodder EM, Barnett P, Ilgun A, Beekman L, van Duijvenboden K, Bokenkamp R, Müller-Nurasyid M, Vliegen HW, Konings TC, van Melle JP, van Dijk AP, van Kimmenade RR, Roos-Hesselink JW, Sieswerda GT, Meijboom F, Abdul-Khaliq H, Berger F, Dittrich S, Hitz MP, Moosmann J, Riede FT, Schubert S, Galan P, Lathrop M, Munter HM, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Veldink JH, van den Berg LH, Evans S, Nobrega MA, Aneas I, Radivojkov-Blagojević M, Meitinger T, Oechslin E, Mondal T, Bergin L, Smythe JF, Altamirano-Diaz L, Lougheed J, Bouma BJ, Chaix MA, Kline J, Bassett AS, Andelfinger G, van der Palen RL, Bouvagnet P, Clur SAB, Breckpot J, Kerstjens-Frederikse WS, Winlaw DS, Bauer UM, Mital S, Goldmuntz E, Keavney B, Bonnet D, Mulder BJ, Tanck MW, Bakkers J, Christoffels VM, Boogerd CJ, Postma AV, Bezzina CR. Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries. Circ Res 2022; 130:166-180. [PMID: 34886679 PMCID: PMC8768504 DOI: 10.1161/circresaha.120.317107] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 12/07/2021] [Accepted: 12/09/2021] [Indexed: 12/21/2022]
Abstract
RATIONALE Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. OBJECTIVE We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. METHODS AND RESULTS We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. CONCLUSIONS This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.
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Affiliation(s)
- Doris Škorić-Milosavljević
- Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, The Netherlands (D.S.-M., R.T., O.I.W., F.V.Y.T., N.L., E.M.L., L.B., B.J.B., B.J.M., C.R.B.)
- Department of Human Genetics, Amsterdam University Medical Centers, The Netherlands (D.S.-M., E.M.L., A.V.P.)
| | - Rafik Tadros
- Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, The Netherlands (D.S.-M., R.T., O.I.W., F.V.Y.T., N.L., E.M.L., L.B., B.J.B., B.J.M., C.R.B.)
- Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada (R.T., M.-A.C.)
| | - Fernanda M. Bosada
- Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands (F.M.B., J.H.v.W., P.B., A.I., K.v.D., V.M.C., A.V.P.)
| | - Federico Tessadori
- Hubrecht Institute-KNAW and University Medical Center Utrecht, the Netherlands (F.T., J.B., C.J.B.)
| | - Jan Hendrik van Weerd
- Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands (F.M.B., J.H.v.W., P.B., A.I., K.v.D., V.M.C., A.V.P.)
| | - Odilia I. Woudstra
- Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, The Netherlands (D.S.-M., R.T., O.I.W., F.V.Y.T., N.L., E.M.L., L.B., B.J.B., B.J.M., C.R.B.)
- Department of Cardiology, University Medical Center Utrecht, The Netherlands (O.I.W., G.T.S., F.M.)
| | - Fleur V.Y. Tjong
- Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, The Netherlands (D.S.-M., R.T., O.I.W., F.V.Y.T., N.L., E.M.L., L.B., B.J.B., B.J.M., C.R.B.)
| | - Najim Lahrouchi
- Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, The Netherlands (D.S.-M., R.T., O.I.W., F.V.Y.T., N.L., E.M.L., L.B., B.J.B., B.J.M., C.R.B.)
| | - Fanny Bajolle
- German Heart Center Berlin, Department of Congenital Heart Disease, Pediatric Cardiology, DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany (F.B., S.S.)
| | - Heather J. Cordell
- Population Health Sciences Institute, Newcastle University, Newcastle, United Kingdom (H.J.C.)
| | - A.J. Agopian
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, UTHealth School of Public Health, Houston, TX (A.J.A.)
| | - Gillian M. Blue
- Heart Centre for Children, The Children’s Hospital at Westmead and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Australia (G.M.B., D.S.W.)
| | | | | | - Christoph Preuss
- Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Québec, Canada (C.P., G.A.)
- The Jackson Laboratory, Bar Harbor, ME (C.P.)
| | - Elisabeth M. Lodder
- Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, The Netherlands (D.S.-M., R.T., O.I.W., F.V.Y.T., N.L., E.M.L., L.B., B.J.B., B.J.M., C.R.B.)
- Department of Human Genetics, Amsterdam University Medical Centers, The Netherlands (D.S.-M., E.M.L., A.V.P.)
| | - Phil Barnett
- Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands (F.M.B., J.H.v.W., P.B., A.I., K.v.D., V.M.C., A.V.P.)
| | - Aho Ilgun
- Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands (F.M.B., J.H.v.W., P.B., A.I., K.v.D., V.M.C., A.V.P.)
| | - Leander Beekman
- Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, The Netherlands (D.S.-M., R.T., O.I.W., F.V.Y.T., N.L., E.M.L., L.B., B.J.B., B.J.M., C.R.B.)
| | - Karel van Duijvenboden
- Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands (F.M.B., J.H.v.W., P.B., A.I., K.v.D., V.M.C., A.V.P.)
| | - Regina Bokenkamp
- Division of Pediatric Cardiology, Department of Pediatrics (R.B., R.L.F.v.d.P.), Leiden University Medical Center, The Netherlands
| | - Martina Müller-Nurasyid
- Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany (M.M.-N.)
- IBE, Faculty of Medicine, LMU Munich, Germany (M.M.-N.)
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany (M.M.-N.)
| | - Hubert W. Vliegen
- Department of Cardiology (H.W.V.), Leiden University Medical Center, The Netherlands
| | - Thelma C. Konings
- Department of Cardiology, Amsterdam University Medical Centers, VU Amsterdam, The Netherlands (T.C.K.)
| | - Joost P. van Melle
- Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands (J.P.v.M.)
| | - Arie P.J. van Dijk
- Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands (A.P.J.v.D., R.R.J.v.K.)
| | - Roland R.J. van Kimmenade
- Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands (A.P.J.v.D., R.R.J.v.K.)
- Department of Cardiology, Maastricht University Medical Center, The Netherlands (R.R.J.v.K.)
| | - Jolien W. Roos-Hesselink
- Department of Cardiology, Erasmus Medical Center, Erasmus University, Rotterdam, The Netherlands (J.W.R.-H.)
| | - Gertjan T. Sieswerda
- Department of Cardiology, University Medical Center Utrecht, The Netherlands (O.I.W., G.T.S., F.M.)
| | - Folkert Meijboom
- Department of Cardiology, University Medical Center Utrecht, The Netherlands (O.I.W., G.T.S., F.M.)
| | - Hashim Abdul-Khaliq
- Saarland University Medical Center, Department of Pediatric Cardiology, Homburg, Germany (H.A.-K.)
| | - Felix Berger
- Unité Médico-Chirurgicale de Cardiologie Congénitale et Pédiatrique, Centre de référence Malformations Cardiaques Congénitales Complexes - M3C, Hôpital Necker Enfants Malades, APHP and Université Paris Descartes, Sorbonne Paris Cité, Paris, France (F.B., D.B.)
- Charité, Universitätsmedizin Berlin, Department for Paediatric Cardiology, Germany (F.B.)
| | - Sven Dittrich
- Department of Pediatric Cardiology, Friedrich-Alexander-University of Erlangen-Nuernberg (FAU), Germany (S.D., J.M.)
| | - Marc-Phillip Hitz
- Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital Schleswig-Holstein/Campus Kiel, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (M.-P.H.)
- Department of Human Genetics, University Medical Center Schleswig-Holstein, Kiel, Germany (M.-P.H.)
| | - Julia Moosmann
- Department of Pediatric Cardiology, Friedrich-Alexander-University of Erlangen-Nuernberg (FAU), Germany (S.D., J.M.)
| | - Frank-Thomas Riede
- Leipzig Heart Center, Department of Pediatric Cardiology, University of Leipzig, Germany (F.-T.R.)
| | - Stephan Schubert
- German Heart Center Berlin, Department of Congenital Heart Disease, Pediatric Cardiology, DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany (F.B., S.S.)
- Heart and Diabetes Center NRW, Center of Congenital Heart Disease, Ruhr-University of Bochum, Bad Oeynhausen, Germany (S.S.)
| | - Pilar Galan
- Sorbonne Paris Nord (Paris 13) University, Inserm U1153, Inrae U1125, Cnam, Nutritional Epidemiology Research Team (EREN), Epidemiology and Statistics Research Center – University of Paris (CRESS), Bobigny, France (P.G.)
| | - Mark Lathrop
- McGill Genome Centre and Department of Human Genetics, McGill University, Montreal, Québec, Canada (M.L., H.M.M.)
| | - Hans M. Munter
- McGill Genome Centre and Department of Human Genetics, McGill University, Montreal, Québec, Canada (M.L., H.M.M.)
| | - Ammar Al-Chalabi
- Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King’s College London, United Kingdom (A.A.-C.)
| | - Christopher E. Shaw
- United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom (C.E.S.)
- Centre for Brain Research, University of Auckland, New Zealand (C.E.S.)
| | - Pamela J. Shaw
- Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield and NIHR Sheffield Biomedical Research Centre for Translational Neuroscience, United Kingdom (P.J.S.)
| | - Karen E. Morrison
- Faculty of Medicine Health & Life Sciences, Queens University Belfast, United Kingdom (K.E.M.)
| | - Jan H. Veldink
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands (J.H.V., L.H.v.d.B.)
| | - Leonard H. van den Berg
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands (J.H.V., L.H.v.d.B.)
| | - Sylvia Evans
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego (S.E.)
| | | | - Ivy Aneas
- Department of Human Genetics, University of Chicago, IL (M.A.N., I.A.)
| | | | - Thomas Meitinger
- Helmholtz Zentrum Munich, Institut of Human Genetics, Neuherberg, Germany (M.R.-B., T.M.)
- Division of Cardiology, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada (T.M.)
| | - Erwin Oechslin
- Peter Munk Cardiac Center, Toronto Congenital Cardiac Centre for Adults and University of Toronto, Canada (E.O.)
| | - Tapas Mondal
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (T.M.)
| | - Lynn Bergin
- Division of Cardiology, Department of Medicine, London Health Sciences Centre, ON, Canada (L.B.)
| | - John F. Smythe
- Division of Cardiology, Department of Pediatrics, Kingston General Hospital, ON, Canada (J.F.S.)
| | | | - Jane Lougheed
- Division of Cardiology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, Canada (J.L.)
| | - Berto J. Bouma
- Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, The Netherlands (D.S.-M., R.T., O.I.W., F.V.Y.T., N.L., E.M.L., L.B., B.J.B., B.J.M., C.R.B.)
| | - Marie-A. Chaix
- Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada (R.T., M.-A.C.)
| | - Jennie Kline
- Department of Epidemiology, Mailman School of Public Health, Columbia University, NY (J.K.)
| | - Anne S. Bassett
- Clinical Genetics Research Program, Centre for Addiction and Mental Health (A.S.B.)
- Department of Psychiatry, University of Toronto, Toronto General Hospital, University Health Network, Ontario, Canada (A.S.B.)
| | - Gregor Andelfinger
- Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Québec, Canada (C.P., G.A.)
| | - Roel L.F. van der Palen
- Division of Pediatric Cardiology, Department of Pediatrics (R.B., R.L.F.v.d.P.), Leiden University Medical Center, The Netherlands
| | - Patrice Bouvagnet
- CPDPN, Hôpital MFME, CHU Martinique, Fort de France, Martinique, France (P.B.)
| | - Sally-Ann B. Clur
- Department of Pediatric Cardiology, Emma Children’s Hospital Amsterdam University Medical Centers (AMC), The Netherlands (S.-A.B.C.)
- Centre for Congenital Heart Disease Amsterdam-Leiden (CAHAL) (S.-A.B.C.)
| | - Jeroen Breckpot
- Hubrecht Institute-KNAW and University Medical Center Utrecht, the Netherlands (F.T., J.B., C.J.B.)
- Center for Human Genetics University Hospitals KU Leuven, Belgium (J.B.)
| | | | - David S. Winlaw
- Heart Centre for Children, The Children’s Hospital at Westmead and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Australia (G.M.B., D.S.W.)
| | - Ulrike M.M. Bauer
- National Register for Congenital Heart Defects, DZHK (German Centre for Cardiovascular Research), Berlin, Germany (U.M.M.B.)
| | - Seema Mital
- Hospital for Sick Children, University of Toronto, Ontario, Canada (S.M.)
| | - Elizabeth Goldmuntz
- Division of Cardiology, Children’s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (E.G.)
| | - Bernard Keavney
- Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester and Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, United Kingdom (B.K.)
| | - Damien Bonnet
- Unité Médico-Chirurgicale de Cardiologie Congénitale et Pédiatrique, Centre de référence Malformations Cardiaques Congénitales Complexes - M3C, Hôpital Necker Enfants Malades, APHP and Université Paris Descartes, Sorbonne Paris Cité, Paris, France (F.B., D.B.)
| | - Barbara J. Mulder
- Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, The Netherlands (D.S.-M., R.T., O.I.W., F.V.Y.T., N.L., E.M.L., L.B., B.J.B., B.J.M., C.R.B.)
| | - Michael W.T. Tanck
- Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health (APH), Amsterdam University Medical Centers, University of Amsterdam, The Netherlands (M.W.T.T.)
| | - Jeroen Bakkers
- Division of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, the Netherlands (J.B.)
| | - Vincent M. Christoffels
- Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands (F.M.B., J.H.v.W., P.B., A.I., K.v.D., V.M.C., A.V.P.)
| | - Cornelis J. Boogerd
- Hubrecht Institute-KNAW and University Medical Center Utrecht, the Netherlands (F.T., J.B., C.J.B.)
| | - Alex V. Postma
- Department of Human Genetics, Amsterdam University Medical Centers, The Netherlands (D.S.-M., E.M.L., A.V.P.)
- Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Cardiovascular Sciences, the Netherlands (F.M.B., J.H.v.W., P.B., A.I., K.v.D., V.M.C., A.V.P.)
| | - Connie R. Bezzina
- Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Heart Center, Amsterdam Cardiovascular Sciences, The Netherlands (D.S.-M., R.T., O.I.W., F.V.Y.T., N.L., E.M.L., L.B., B.J.B., B.J.M., C.R.B.)
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Martínez-Gil N, Ugartondo N, Grinberg D, Balcells S. Wnt Pathway Extracellular Components and Their Essential Roles in Bone Homeostasis. Genes (Basel) 2022; 13:genes13010138. [PMID: 35052478 PMCID: PMC8775112 DOI: 10.3390/genes13010138] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/10/2022] [Accepted: 01/11/2022] [Indexed: 12/11/2022] Open
Abstract
The Wnt pathway is involved in several processes essential for bone development and homeostasis. For proper functioning, the Wnt pathway is tightly regulated by numerous extracellular elements that act by both activating and inhibiting the pathway at different moments. This review aims to describe, summarize and update the findings regarding the extracellular modulators of the Wnt pathway, including co-receptors, ligands and inhibitors, in relation to bone homeostasis, with an emphasis on the animal models generated, the diseases associated with each gene and the bone processes in which each member is involved. The precise knowledge of all these elements will help us to identify possible targets that can be used as a therapeutic target for the treatment of bone diseases such as osteoporosis.
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Samanta S, Mahata R, Santra MK. The Cross-Talk between Epigenetic Gene Regulation and Signaling Pathways Regulates Cancer Pathogenesis. Subcell Biochem 2022; 100:427-472. [PMID: 36301502 DOI: 10.1007/978-3-031-07634-3_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Cancer begins due to uncontrolled cell division. Cancer cells are insensitive to the signals that control normal cell proliferation. This uncontrolled cell division is due to the accumulation of abnormalities in different factors associated with the cell division, including different cyclins, cell cycle checkpoint inhibitors, and cellular signaling. Cellular signaling pathways are aberrantly activated in cancer mainly due to epigenetic regulation and post-translational regulation. In this chapter, the role of epigenetic regulation in aberrant activation of PI3K/AKT, Ras, Wnt, Hedgehog, Notch, JAK/STAT, and mTOR signaling pathways in cancer progression is discussed. The role of epigenetic regulators in controlling the upstream regulatory proteins and downstream effector proteins responsible for abnormal cellular signaling-mediated cancer progression is covered in this chapter. Similarly, the role of signaling pathways in controlling epigenetic gene regulation-mediated cancer progression is also discussed. We have tried to ascertain the current status of potential epigenetic drugs targeting several epigenetic regulators to prevent different cancers.
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Affiliation(s)
- Snigdha Samanta
- Molecular Oncology Laboratory, National Centre for Cell Science, NCCS Complex, S. P. Pune University Campus, Ganeshkhind Road, Pune, Maharashtra, India
- Department of Biotechnology, Savitribai Phule Pune University, Pune, Maharashtra, India
| | - Rumpa Mahata
- Molecular Oncology Laboratory, National Centre for Cell Science, NCCS Complex, S. P. Pune University Campus, Ganeshkhind Road, Pune, Maharashtra, India
- Department of Biotechnology, Savitribai Phule Pune University, Pune, Maharashtra, India
| | - Manas Kumar Santra
- Molecular Oncology Laboratory, National Centre for Cell Science, NCCS Complex, S. P. Pune University Campus, Ganeshkhind Road, Pune, Maharashtra, India.
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44
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Čada Š, Bryja V. Local Wnt signalling in the asymmetric migrating vertebrate cells. Semin Cell Dev Biol 2021; 125:26-36. [PMID: 34896020 DOI: 10.1016/j.semcdb.2021.11.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 11/27/2022]
Abstract
Wnt signalling is known to generate cellular asymmetry via Wnt/planar cell polarity pathway (Wnt/PCP). Wnt/PCP acts locally (i) to orient membrane polarity and asymmetric establishment of intercellular junctions via conserved set of PCP proteins most specifically represented by Vangl and Prickle, and (ii) to asymmetrically rearrange cytoskeletal structures via downstream effectors of Dishevelled (Dvl). This process is best described on stable phenotypes of epithelial cells. Here, however, we review the activity of Wnt signalling in migratory cells which experience the extensive rearrangements of cytoskeleton and consequently dynamic asymmetry, making the localised effects of Wnt signalling easier to distinguish. Firstly, we focused on migration of neuronal axons, which allows to study how the pre-existent cellular asymmetry can influence Wnt signalling outcome. Then, we reviewed the role of Wnt signalling in models of mesenchymal migration including neural crest, melanoma, and breast cancer cells. Last, we collected evidence for local Wnt signalling in amoeboid cells, especially lymphocytes. As the outcome of this review, we identify blank spots in our current understanding of this topic, propose models that synthesise the current observations and allow formulation of testable hypotheses for the future research.
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Affiliation(s)
- Štěpán Čada
- Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic
| | - Vítězslav Bryja
- Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic; Department of Cytokinetics, Institute of Biophysics CAS, Královopolská 135, 61265 Brno, Czech Republic.
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45
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Han YM, Gao H, Hua RX, Liang C, Guo YX, Shang HW, Lu X, Xu JD. Paneth cells and intestinal health. Shijie Huaren Xiaohua Zazhi 2021; 29:1362-1372. [DOI: 10.11569/wcjd.v29.i23.1362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Paneth cells (PC) are a group of secretory cells derived from intestinal stem cells (ISC) and colonized in the bottom of the small intestinal crypt. As an important "guardian" of intestinal health, PC can not only secrete a variety of antibacterial peptides and cytokines to regulate intestinal homeostasis and participate in immune responses, but also release growth factors to support the stem cell niche and regulate their proliferation and differentiation. Of particular concern, as a static stem cell pool, PC can acquire a stem cell-like transcriptome after the injury of intestinal tissue so as to promote regeneration and repair the damaged intestinal tissue. Particularly, PC are closely related to a number of diseases that affect intestinal health, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). The research of biological functions of PC may provide ideas for the treatment of these diseases. In summary, the role of PC in maintaining intestinal health should not be underestimated.
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Affiliation(s)
- Yi-Min Han
- 2019 Oral Medicine, Capital Medical University, Beijing 100069, China
| | - Han Gao
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
| | - Rong-Xuan Hua
- 2020 Clinical Medicine of "5+3" Program, Capital Medical University, Beijing 100069, China
| | - Chen Liang
- Clinical Medicine, Capital Medical University, Beijing 100069, China
| | - Yue-Xin Guo
- 2019 Oral Medicine of "5+3" Program, Capital Medical University, Beijing 100069, China
| | - Hong-Wei Shang
- Experimental Teaching Center of Basic Medical Morphology, Capital Medical University, Beijing 100069, China
| | - Xin Lu
- Experimental Teaching Center of Basic Medical Morphology, Capital Medical University, Beijing 100069, China
| | - Jing-Dong Xu
- Department of Physiology and Pathophysiology, Capital Medical University, Beijing 100069, China
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46
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Kosar K, Cornuet P, Singh S, Lee E, Liu S, Gayden J, Sato T, Freyberg Z, Arteel G, Nejak‐Bowen K. WNT7B Regulates Cholangiocyte Proliferation and Function During Murine Cholestasis. Hepatol Commun 2021; 5:2019-2034. [PMID: 34558852 PMCID: PMC8631094 DOI: 10.1002/hep4.1784] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/25/2021] [Accepted: 06/14/2021] [Indexed: 12/16/2022] Open
Abstract
We previously identified an up-regulation of specific Wnt proteins in the cholangiocyte compartment during cholestatic liver injury and found that mice lacking Wnt secretion from hepatocytes and cholangiocytes showed fewer proliferating cholangiocytes and high mortality in response to a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet, a murine model of primary sclerosing cholangitis. In vitro studies demonstrated that Wnt7b, one of the Wnts up-regulated during cholestasis, induces proliferation of cholangiocytes in an autocrine manner and increases secretion of proinflammatory cytokines. We hypothesized that loss of Wnt7b may exacerbate some of the complications of cholangiopathies by decreasing the ability of bile ducts to induce repair. Wnt7b-flox mice were bred with Krt19-cre mice to deplete Wnt7b expression in only cholangiocytes (CC) or with albumin-Cre mice to delete Wnt7b expression in both hepatocytes and cholangiocytes (HC + CC). These mice were placed on a DDC diet for 1 month then killed for evaluation. Contrary to our expectations, we found that mice lacking Wnt7b from CC and HC + CC compartments had improved biliary injury, decreased cellular senescence, and lesser bile acid accumulation after DDC exposure compared to controls, along with decreased expression of inflammatory cytokines. Although Wnt7b knockout (KO) resulted in fewer proliferating cholangiocytes, CC and HC + CC KO mice on a DDC diet also had more hepatocytes expressing cholangiocyte markers compared to wild-type mice on a DDC diet, indicating that Wnt7b suppression promotes hepatocyte reprogramming. Conclusion: Wnt7b induces a proproliferative proinflammatory program in cholangiocytes, and its loss is compensated for by conversion of hepatocytes to a biliary phenotype during cholestatic injury.
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Affiliation(s)
- Karis Kosar
- Department of PathologyUniversity of PittsburghPittsburghPAUSA
| | - Pamela Cornuet
- Department of PathologyUniversity of PittsburghPittsburghPAUSA
| | - Sucha Singh
- Department of PathologyUniversity of PittsburghPittsburghPAUSA
| | - Elizabeth Lee
- Department of PathologyUniversity of PittsburghPittsburghPAUSA
| | - Silvia Liu
- Department of PathologyUniversity of PittsburghPittsburghPAUSA
- Pittsburgh Liver Research CenterUniversity of PittsburghPittsburghPAUSA
| | - Jenesis Gayden
- Department of PsychiatryUniversity of PittsburghPittsburghPAUSA
| | - Toshifumi Sato
- Department of MedicineGastroenterology DivisionUniversity of PittsburghPittsburghPAUSA
| | - Zachary Freyberg
- Pittsburgh Liver Research CenterUniversity of PittsburghPittsburghPAUSA
- Department of PsychiatryUniversity of PittsburghPittsburghPAUSA
- Department of Cell BiologyUniversity of PittsburghPittsburghPAUSA
| | - Gavin Arteel
- Pittsburgh Liver Research CenterUniversity of PittsburghPittsburghPAUSA
- Department of MedicineGastroenterology DivisionUniversity of PittsburghPittsburghPAUSA
| | - Kari Nejak‐Bowen
- Department of PathologyUniversity of PittsburghPittsburghPAUSA
- Pittsburgh Liver Research CenterUniversity of PittsburghPittsburghPAUSA
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47
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Astudillo P. An emergent Wnt5a/YAP/TAZ regulatory circuit and its possible role in cancer. Semin Cell Dev Biol 2021; 125:45-54. [PMID: 34764023 DOI: 10.1016/j.semcdb.2021.10.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/04/2021] [Accepted: 10/07/2021] [Indexed: 12/29/2022]
Abstract
Wnt5a is a ligand that plays several roles in development, homeostasis, and disease. A growing body of evidence indicates that Wnt5a is involved in cancer progression. Despite extensive research in this field, our knowledge about how Wnt5a is precisely involved in cancer is still incomplete. It is usually thought that certain combinations of Frizzled receptors and co-receptors might explain the observed effects of Wnt5a either as a tumor suppressor or by promoting migration and invasion. While accepting this 'receptor context' model, this review proposes that Wnt5a is integrated within a larger regulatory circuit involving β-catenin, YAP/TAZ, and LATS1/2. Remarkably, WNT5A and YAP1 are transcriptionally regulated by the Hippo and Wnt pathways, respectively, and might form a regulatory circuit acting through LATS kinases and secreted Wnt/β-catenin inhibitors, including Wnt5a itself. Therefore, understanding the precise role of Wnt5a and YAP in cancer requires a systems biology perspective.
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Affiliation(s)
- Pablo Astudillo
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile.
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48
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The concurrent stimulation of Wnt and FGF8 signaling induce differentiation of dental mesenchymal cells into odontoblast-like cells. Med Mol Morphol 2021; 55:8-19. [PMID: 34739612 PMCID: PMC8885561 DOI: 10.1007/s00795-021-00297-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 06/13/2021] [Indexed: 11/05/2022]
Abstract
Fibroblast growth factor 8 (FGF8) is known to be a potent stimulator of canonical Wnt/β-catenin activity, an essential factor for tooth development. In this study, we analyzed the effects of co-administration of FGF8 and a CHIR99021 (GSK3β inhibitor) on differentiation of dental mesenchymal cells into odontoblasts. Utilizing Cre-mediated EGFP reporter mice, dentin matrix protein 1 (Dmp1) expression was examined in mouse neonatal molar tooth germs. At birth, expression of Dmp1-EGFP was not found in mesenchymal cells but rather epithelial cells, after which Dmp1-positive cells gradually emerged in the mesenchymal area along with disappearance in the epithelial area. Primary cultured mesenchymal cells from neonatal tooth germ specimens showed loss of Dmp1-EGFP positive signals, whereas addition of Wnt3a or the CHIR99021 significantly regained Dmp1 positivity within approximately 2 weeks. Other odontoblast markers such as dentin sialophosphoprotein (Dspp) could not be clearly detected. Concurrent stimulation of primary cultured mesenchymal cells with the CHIR99021 and FGF8 resulted in significant upregulation of odonto/osteoblast proteins. Furthermore, increased expression levels of runt-related transcription factor 2 (Runx2), osterix, and osteocalcin were also observed. The present findings indicate that coordinated action of canonical Wnt/β-catenin and FGF8 signals is essential for odontoblast differentiation of tooth germs in mice.
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49
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Wang L, Li J, Di LJ. Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases. Med Res Rev 2021; 42:946-982. [PMID: 34729791 PMCID: PMC9298385 DOI: 10.1002/med.21867] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 08/01/2021] [Accepted: 10/24/2021] [Indexed: 12/19/2022]
Abstract
Glycogen synthase kinase‐3 (GSK3) is a highly evolutionarily conserved serine/threonine protein kinase first identified as an enzyme that regulates glycogen synthase (GS) in response to insulin stimulation, which involves GSK3 regulation of glucose metabolism and energy homeostasis. Both isoforms of GSK3, GSK3α, and GSK3β, have been implicated in many biological and pathophysiological processes. The various functions of GSK3 are indicated by its widespread distribution in multiple cell types and tissues. The studies of GSK3 activity using animal models and the observed effects of GSK3‐specific inhibitors provide more insights into the roles of GSK3 in regulating energy metabolism and homeostasis. The cross‐talk between GSK3 and some important energy regulators and sensors and the regulation of GSK3 in mitochondrial activity and component function further highlight the molecular mechanisms in which GSK3 is involved to regulate the metabolic activity, beyond its classical regulatory effect on GS. In this review, we summarize the specific roles of GSK3 in energy metabolism regulation in tissues that are tightly associated with energy metabolism and the functions of GSK3 in the development of metabolic disorders. We also address the impacts of GSK3 on the regulation of mitochondrial function, activity and associated metabolic regulation. The application of GSK3 inhibitors in clinical tests will be highlighted too. Interactions between GSK3 and important energy regulators and GSK3‐mediated responses to different stresses that are related to metabolism are described to provide a brief overview of previously less‐appreciated biological functions of GSK3 in energy metabolism and associated diseases through its regulation of GS and other functions.
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Affiliation(s)
- Li Wang
- Proteomics, Metabolomics, and Drug Development Core, Faculty of Health Sciences, University of Macau, Macau, China.,Department of Biomedical Sciences, Faculty of Health Sciences, Macau, China.,Cancer Center of the Faculty of Health Sciences, University of Macau, Macau, China.,Institute of Translational Medicine, University of Macau, Macau, China.,Ministry of Education, Frontiers Science Center for Precision Oncology, University of Macau, Macau, China
| | - Jiajia Li
- Department of Biomedical Sciences, Faculty of Health Sciences, Macau, China.,Cancer Center of the Faculty of Health Sciences, University of Macau, Macau, China.,Institute of Translational Medicine, University of Macau, Macau, China.,Ministry of Education, Frontiers Science Center for Precision Oncology, University of Macau, Macau, China
| | - Li-Jun Di
- Department of Biomedical Sciences, Faculty of Health Sciences, Macau, China.,Cancer Center of the Faculty of Health Sciences, University of Macau, Macau, China.,Institute of Translational Medicine, University of Macau, Macau, China.,Ministry of Education, Frontiers Science Center for Precision Oncology, University of Macau, Macau, China
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50
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Bell IJ, Horn MS, Van Raay TJ. Bridging the gap between non-canonical and canonical Wnt signaling through Vangl2. Semin Cell Dev Biol 2021; 125:37-44. [PMID: 34736823 DOI: 10.1016/j.semcdb.2021.10.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/30/2021] [Accepted: 10/05/2021] [Indexed: 12/29/2022]
Abstract
Non-canonical Wnt signaling (encompassing Wnt/PCP and WntCa2+) has a dual identity in the literature. One stream of research investigates its role in antagonizing canonical Wnt/β-catenin signaling in cancer, typically through Ca2+, while the other stream investigates its effect on polarity in development, typically through Vangl2. Rarely do these topics intersect or overlap. What has become clear is that Wnt5a can mobilize intracellular calcium stores to inhibit Wnt/β-catenin in cancer cells but there is no evidence that Vangl2 is involved in this process. Conversely, Wnt5a can independently activate Vangl2 to affect polarity and migration but the role of calcium in this process is also limited. Further, Vangl2 has also been implicated in inhibiting Wnt/β-catenin signaling in development. The consensus is that a cell can differentiate between canonical and non-canonical Wnt signaling when presented with a choice, always choosing non-canonical at the expense of canonical Wnt signaling. However, these are rare events in vivo. Given the shared resources between non-canonical and canonical Wnt signaling it is perplexing that there is not more in vivo evidence for cross talk between these two pathways. In this review we discuss the intersection of non-canonical Wnt, with a focus on Wnt/PCP, and Wnt/β-catenin signaling in an attempt to shed some light on pathways that rarely meet at a crossroads in vivo.
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Affiliation(s)
- Ian James Bell
- Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Rd. E, Guelph, ON, Canada N1G 2W1
| | - Matthew Sheldon Horn
- Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Rd. E, Guelph, ON, Canada N1G 2W1
| | - Terence John Van Raay
- Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Rd. E, Guelph, ON, Canada N1G 2W1.
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