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Sharma A, Vijay N. Common Ancestry of the Id Locus: Chromosomal Rearrangement and Polygenic Possibilities. J Mol Evol 2025; 93:163-180. [PMID: 39821315 DOI: 10.1007/s00239-025-10233-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: 03/20/2024] [Accepted: 12/30/2024] [Indexed: 01/19/2025]
Abstract
The diversity in dermal pigmentation and plumage color among domestic chickens is striking, with Black Bone Chickens (BBC) particularly notable for their intense melanin hyperpigmentation. This unique trait is driven by a complex chromosomal rearrangement on chromosome 20 at the Fm locus, resulting in the overexpression of the EDN3 (a gene central to melanocyte regulation). In contrast, the inhibition of dermal pigmentation is regulated by the Id locus. Although prior studies using genetic crosses, GWAS, and gene expression analysis have investigated the genetic underpinnings of the Id locus, its precise location and functional details remain elusive. Our study aims to precisely locate the Id locus, identify associated chromosomal rearrangements and candidate genes influencing dermal pigmentation, and examine the ancestral status of the Id locus in BBC breeds. Using public genomic data from BBC and non-BBC breeds, we refined the Id locus to a ~1.6 Mb region that co-localizes with Z amplicon repeat units at the distal end of the q-arm of chromosome Z within a 10.36 Mb inversion in Silkie BBC. Phylogenetic and population structure analyses reveal that the Id locus shares a common ancestry across all BBC breeds, much like the Fm locus. Selection signatures and highly differentiated BBC-specific SNPs within the MTAP gene position it as the prime candidate for the Id locus with CCDC112 and additional genes, suggesting a possible polygenic nature. Our results suggest that the Id locus is shared among BBC breeds and may function as a supergene cluster in shank and dermal pigmentation variation.
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Affiliation(s)
- Ashutosh Sharma
- Computational Evolutionary Genomics Lab, Department of Biological Sciences, IISER Bhopal, Bhauri, Madhya Pradesh, India
| | - Nagarjun Vijay
- Computational Evolutionary Genomics Lab, Department of Biological Sciences, IISER Bhopal, Bhauri, Madhya Pradesh, India.
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Butler Tjaden NE, Shannon SR, Seidel CW, Childers M, Aoto K, Sandell LL, Trainor PA. Rdh10-mediated Retinoic Acid Signaling Regulates the Neural Crest Cell Microenvironment During ENS Formation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.23.634504. [PMID: 39896510 PMCID: PMC11785139 DOI: 10.1101/2025.01.23.634504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
The enteric nervous system (ENS) is formed from vagal neural crest cells (NCC), which generate most of the neurons and glia that regulate gastrointestinal function. Defects in the migration or differentiation of NCC in the gut can result in gastrointestinal disorders such as Hirschsprung disease (HSCR). Although mutations in many genes have been associated with the etiology of HSCR, a significant proportion of affected individuals have an undetermined genetic diagnosis. Therefore, it's important to identify new genes, modifiers and environmental factors that regulate ENS development and disease. Rdh10 catalyzes the first oxidative step in the metabolism of vitamin A to its active metabolite, RA, and is therefore a central regulator of vitamin A metabolism and retinoic acid (RA) synthesis during embryogenesis. We discovered that retinol dehydrogenase 10 (Rdh10) loss-of-function mouse embryos exhibit intestinal aganglionosis, characteristic of HSCR. Vagal NCC form and migrate in Rdh10 mutant embryos but fail to invade the foregut. Rdh10 is highly expressed in the mesenchyme surrounding the entrance to the foregut and is essential between E7.5-E9.5 for NCC invasion into the gut. Comparative RNA-sequencing revealed downregulation of the Ret-Gdnf-Gfrα1 gene signaling network in Rdh10 mutants, which is critical for vagal NCC chemotaxis. Furthermore, the composition of the extracellular matrix through which NCC migrate is also altered, in part by increased collagen deposition. Collectively this restricts NCC entry into the gut, demonstrating that Rdh10-mediated vitamin A metabolism and RA signaling pleiotropically regulates the NCC microenvironment during ENS formation and in the pathogenesis of intestinal aganglionosis.
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Affiliation(s)
- Naomi E. Butler Tjaden
- Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Gastroenterology, Hepatology & Nutrition, Children’s Hospital of Philadelphia, Philadelphia PA 19104
| | - Stephen R. Shannon
- Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | | | - Melissa Childers
- Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA
| | - Kazushi Aoto
- Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu City, Shizuoka, Japan 431-3192
| | - Lisa L. Sandell
- University of Louisville, Department of Oral Immunology and Infectious Diseases, Louisville, KY, 40201, USA
| | - Paul A. Trainor
- Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Fries LE, Grullon G, Berk-Rauch HE, Chakravarti A, Chatterjee S. Synergistic effects of Ret coding and enhancer loss-of-function alleles cause progressive loss of inhibitory motor neurons in the enteric nervous system. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.23.634550. [PMID: 39896597 PMCID: PMC11785208 DOI: 10.1101/2025.01.23.634550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
Coding and enhancer variants of the RET receptor tyrosine kinase gene contribute to ~50% of Hirschsprung disease (HSCR) risk, a congenital disorder of disrupted enteric nervous system (ENS) development. The greatest contribution of this risk is from a common variant (rs2435357) in an ENS-active, SOX10-bound RET enhancer (MCS+9.7) that reduces RET gene expression in vivo and triggers expression changes in other ENS genes in the human fetal gut. To uncover the cellular basis of RET-mediated aganglionosis, we used CRISPR/Cas9 to delete (Δ) the homologous mouse enhancer (mcs+9.7). We used single cell RNA sequencing and high-resolution immunofluorescence to demonstrate four significant features of the developing E14.5 gut of Δmcs+9.7/Δmcs+9.7 embryos: (1) a small (5%) yet significant reduction in Ret gene expression in only two major cell types - early differentiating neurons and fate-restricted inhibitory motor neurons; (2) no significant cellular loss in the ENS; and, (3) loss of expression of 19 cell cycle regulator genes suggesting a proliferative defect. To identify the Ret functional threshold for normal ENS development, we also generated, in combination with the Ret CFP null allele, (4) Δmcs+9.7/CFP double heterozygote mice which reduced Ret gene expression in the ENS to 42% with severe loss of inhibitory motor neurons, an effect restricted to the hindgut and driven by proliferative loss. Thus, Ret gene expression drives proliferation of ENS progenitor cells and hindgut-specific inhibitory motor neuron development, and that HSCR aganglionosis arises from a cascade of cellular defects triggered by >50% loss of Ret function.
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Affiliation(s)
- Lauren E Fries
- Center for Human Genetics & Genomics, New York University Grossman School of Medicine, New York, NY 10016
| | - Gabriel Grullon
- Center for Human Genetics & Genomics, New York University Grossman School of Medicine, New York, NY 10016
| | - Hanna E Berk-Rauch
- Center for Human Genetics & Genomics, New York University Grossman School of Medicine, New York, NY 10016
| | - Aravinda Chakravarti
- Center for Human Genetics & Genomics, New York University Grossman School of Medicine, New York, NY 10016
- Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY 10016
| | - Sumantra Chatterjee
- Center for Human Genetics & Genomics, New York University Grossman School of Medicine, New York, NY 10016
- Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY 10016
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Herbet A, Hautière M, Jean-Alphonse F, Vivier D, Leboeuf C, Costa N, Mabondzo A, Bousquet G, Denat F, Reiter E, Boquet D. Targeting the activated allosteric conformation of the endothelin receptor B in melanoma with an antibody-drug conjugate: mechanisms and therapeutic efficacy. BJC REPORTS 2025; 3:3. [PMID: 39833448 PMCID: PMC11747117 DOI: 10.1038/s44276-024-00109-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/02/2024] [Accepted: 10/13/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Endothelin 1 receptors are one of the drivers of tumor progression in many cancers. Inhibition of their signaling pathways with antagonist drugs has been the subject of numerous clinical trials, but the results have not met expectations probably due to the high endothelin concentrations in the tumor microenvironment and their unusually high affinity for their receptors. METHODS We previously reported the rendomab B49 antibody (RB49) exhibiting a preferential affinity for the activated conformation of human endothelin B receptor (ETB), not displaced by high endothelin levels, and without any pharmacological properties that could inhibit the division of melanoma cells. In this context, we have developed xiRB49-MMAE, a chimeric antibody-drug conjugated (ADC) to monomethyl auristatin E. We have characterized its physicochemical properties, studied its binding mechanisms, and evaluated its therapeutic potential in a preclinical model. Immunohistochemical analysis of metastatic melanoma lymph nodes evaluated RB49 as a diagnostic tool for patient stratification. RESULTS xiRB49-MMAE showed high efficacy against melanoma cells and ETB+ xenograft tumor models. IHC studies indicated that 100% of melanoma patient lymph node biopsies were RB49-positive. CONCLUSIONS xiRB49-MMAE is a promising drug candidate for clinical trials in ETB+ tumors. RB49 could be used as a diagnostic tool for patient stratification.
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Affiliation(s)
- Amaury Herbet
- Université Paris-Saclay, CEA, INRAE, Médicaments et Technologies pour la Santé (MTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire et Innovation Thérapeutique (LENIT), Gif-sur-Yvette, France
| | - Marie Hautière
- Université Paris-Saclay, CEA, INRAE, Médicaments et Technologies pour la Santé (MTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire et Innovation Thérapeutique (LENIT), Gif-sur-Yvette, France
| | - Frédéric Jean-Alphonse
- INRAE, CNRS, Université de Tours, PRC, Nouzilly, France
- Inria, Inria Saclay-Ile-de-France, Palaiseau, France
| | - Delphine Vivier
- Institut de Chimie Moléculaire de l'Université de Bourgogne, ICMUB UMR CNRS 6302, Université de Bourgogne, Dijon, France
| | | | - Narciso Costa
- Université Paris-Saclay, CEA, INRAE, Médicaments et Technologies pour la Santé (MTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire et Innovation Thérapeutique (LENIT), Gif-sur-Yvette, France
| | - Aloïse Mabondzo
- Université Paris-Saclay, CEA, INRAE, Médicaments et Technologies pour la Santé (MTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire et Innovation Thérapeutique (LENIT), Gif-sur-Yvette, France
| | - Guilhem Bousquet
- Université Paris Cité, INSERM, UMR_S942 MASCOT, Paris, France
- Université Sorbonne Paris Nord, Villetaneuse, France
| | - Franck Denat
- Inria, Inria Saclay-Ile-de-France, Palaiseau, France
| | - Eric Reiter
- INRAE, CNRS, Université de Tours, PRC, Nouzilly, France
- Inria, Inria Saclay-Ile-de-France, Palaiseau, France
| | - Didier Boquet
- Université Paris-Saclay, CEA, INRAE, Médicaments et Technologies pour la Santé (MTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire et Innovation Thérapeutique (LENIT), Gif-sur-Yvette, France.
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Mutchler AL, Zhong J, Yang HC, Zhao S, Crescenzi R, Taylor S, Rao RL, Shelton EL, Kirabo A, Kon V. ET-3/ETBR Mediates Na +-Activated Immune Signaling and Kidney Lymphatic Dynamics. Circ Res 2025; 136:194-208. [PMID: 39676651 PMCID: PMC11800760 DOI: 10.1161/circresaha.124.324890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 11/14/2024] [Accepted: 12/02/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND Lymphatic collecting vessels in the kidney are critical in clearing interstitial fluid, macromolecules, and infiltrating immune cells. Dysfunction of the lymphatic vessels can disrupt this process and exacerbate injury-associated inflammation in many disease conditions. We previously found that sodium accumulates within the kidney interstitium during proteinuric kidney injury and elevated sodium environments stimulate isolevuglandin production in antigen-presenting cells, stimulating T cells, and modulating inflammatory responses. In the present study, we investigated whether proteinuric injury increases production of isolevuglandin-adduct formation in antigen-presenting cells, their effects on lymphatic endothelial cells (LECs), and the role of the ET-3 (endothelin-3)/ETBR (endothelin type B receptor) on lymphatic vessel function. METHODS We used a mouse model of nephrotoxin-induced proteinuric injury to show that proteinuric injury expanded the kidney lymphatic network and to immunophenotype the infiltrating immune cells. To determine mechanisms, we analyzed the interaction of migratory immune cells and LECs using an in vitro transwell migration assay, bulk RNA sequencing, and flow cytometric analysis. To determine the effect of ET-3/ETBR axis on lymphatic vessel contractility, we analyzed microdissected lymphangions utilizing a vessel perfusion chamber. RESULTS We found that animals with proteinuric injury have increased kidney lymphangiogenesis, isolevuglandin-producing dendritic cells, and IFN (interferon)-γ-producing CD4+T cells. The sodium avid environment present in kidney injury enhances the interaction between LECs and migratory antigen-presenting cells and LEC production of isolevuglandin-adducts. Elevated sodium environment-induced isolevuglandin-adduct formation facilitates the ET-3/ETBR communication between LECs and dendritic cells. In addition, the ET-3/ETBR axis modulates lymphatic collecting vessel pumping dynamics. CONCLUSIONS These findings reveal a novel mechanism linking the isolevuglandin-mediated ET-3/ETBR axis with LECs and infiltrating dendritic cells. ET-3/ETBR signaling in lymphatic vessel dynamics is a novel pathogenic component and a possible therapeutic target in kidney disease.
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Affiliation(s)
- Ashley L. Mutchler
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jianyong Zhong
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Hai-Chun Yang
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Shilin Zhao
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Rachelle Crescenzi
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA
- Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Shannon Taylor
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA
| | - Roy L. Rao
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Elaine L. Shelton
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Annet Kirabo
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Valentina Kon
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Tan J, Duron A, Sucov HM, Makita T. Placode and neural crest origins of congenital deafness in mouse models of Waardenburg-Shah syndrome. iScience 2025; 28:111680. [PMID: 39868048 PMCID: PMC11762213 DOI: 10.1016/j.isci.2024.111680] [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: 03/19/2024] [Revised: 07/19/2024] [Accepted: 12/20/2024] [Indexed: 01/28/2025] Open
Abstract
Mutations in the human genes encoding the endothelin ligand-receptor pair EDN3 and EDNRB cause Waardenburg-Shah syndrome (WS4), which includes congenital hearing impairment. The current explanation for auditory dysfunction is defective migration of neural crest-derived melanocytes to the inner ear. We explored the role of endothelin signaling in auditory development in mice using neural crest-specific and placode-specific Ednrb mutation plus related genetic resources. On an outbred strain background, we find a normal representation of melanocytes in hearing-impaired mutant mice. Instead, our results in neural crest-specific Ednrb mutants implicate a previously unrecognized role for glial support of synapse assembly between auditory neurons and cochlear hair cells. Placode-specific Ednrb mutation also caused impaired hearing, resulting from deficient synaptic transmission. Our observations demonstrate the significant influence of genetic modifiers in auditory development, and invoke independent and separable roles for endothelin signaling in the neural crest and placode lineages to create a functional auditory circuitry.
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Affiliation(s)
- Jaime Tan
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Alicia Duron
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Henry M. Sucov
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Takako Makita
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
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Xiao J, Feng C, Zhu T, Zhang X, Chen X, Li Z, You J, Wang Q, Zhuansun D, Meng X, Wang J, Xiang L, Yu X, Zhou B, Tang W, Tou J, Wang Y, Yang H, Yu L, Liu Y, Jiang X, Ren H, Yu M, Chen Q, Yin Q, Liu X, Xu Z, Wu D, Yu D, Wu X, Yang J, Xiong B, Chen F, Hao X, Feng J. Rare and common genetic variants underlying the risk of Hirschsprung's disease. Hum Mol Genet 2025:ddae205. [PMID: 39817569 DOI: 10.1093/hmg/ddae205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 12/17/2024] [Accepted: 12/27/2024] [Indexed: 01/18/2025] Open
Abstract
Hirschsprung's disease (HSCR) is a congenital enteric neuropathic disorder characterized by high heritability (>80%) and polygenic inheritance (>20 genes). The previous genome-wide association studies (GWAS) identified several common variants associated with HSCR and demonstrated increased predictive performance for HSCR risk in Europeans using a genetic risk score, there remains a notable gap in knowledge regarding Chinese populations. We conducted whole exome sequencing in a HSCR case cohort in Chinese. By using the common controls (505 controls from 1KG EAS and 10 588 controls from ChinaMAP), we conducted GWAS for the common variants in the exome and gene-based association for rare variants. We further validated the associated variants and genes in replicated samples and in vitro and vivo experiments. We identified one novel gene PLK5 by GWAS and suggested 45 novel putative genes based the gene-based test. By using genetic variant at RET and PLK5, we constructed a genetic risk score that could identify the individuals with very high genetic risk for HSCR. Compared with patients with zero or one risk allele from the three variants, the risk for HSCR was 36.61 times higher with six alleles. In addition, we delineated a HSCR risk gene landscape that encompasses 57 genes, which explains 88.5% and 54.5% of HSCR in Chinese and European, respectively. In summary, this study improved the understanding of genetic architecture of HSCR and provided a risk prediction approach for HSCR in the Chinese.
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Affiliation(s)
- Jun Xiao
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Chenzhao Feng
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Tianqi Zhu
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Xuan Zhang
- Department of Pediatric Surgery, Pingshan District Maternal & Child Healthcare Hospital of Shenzhen, No. 6 Longtian South Road, Longtian Subdistrict, Pingshan District, Shenzhen, Guangdong 518122, China
| | - Xuyong Chen
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Zejian Li
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Jingyi You
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Qiong Wang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Didi Zhuansun
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Xinyao Meng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Jing Wang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Lei Xiang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Xiaosi Yu
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Bingyan Zhou
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Weibing Tang
- Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, No. 72 Guangzhou Road, Gulou District, Nanjing, Jiangsu 210008, China
| | - Jinfa Tou
- Department of General Surgery, Children's Hospital, Zhejiang University School of Medicine, No. 3333 Binsheng Road, Binjiang District, Hangzhou, Zhejiang 310003, China
| | - Yi Wang
- Department of General and Neonatal Surgery, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan 2nd Road, Yuzhong District, Chongqing 400014, China
| | - Heying Yang
- Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, No. 1 Renmin Road, Erqi District, Henan 450052, China
| | - Lei Yu
- Department of Neonatal Surgery, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 100 Hong Kong Road, Jiang'an District, Wuhan, Hubei 430030, China
| | - Yuanmei Liu
- Department of Pediatric Surgery, The Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Huichuan District, Zunyi, Guizhou 563000, China
| | - Xuewu Jiang
- Department of Pediatric Surgery, The Second Affiliated Hospital of Shantou University Medical College, No. 69, Dongxia North Road, Jinping District, Shantou, Guangdong 515041, China
| | - Hongxia Ren
- Department of Neonatal Surgery, Children's Hospital of Shanxi, No. 13 Xinminbei Street, Xinhualing district, Taiyuan, Shanxi 030013, China
| | - Mei Yu
- Department of Pediatric Surgery, Guiyang Maternal and Child Health Hospital, No. 63 Ruijin South Road, Nanming district, Guiyang, Guizhou 550002, China
| | - Qi Chen
- Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, No. 7 Kangfuqian Street, Erqi District, Zhengzhou 450052, Henan, China
| | - Qiang Yin
- Department of General Surgery, Hunan Children's Hospital, No. 86 Ziyuan Road, Yuhua District, Changsha, Hunan 515041, China
| | - Xiang Liu
- Department of Pediatric Surgery, Anhui Provincial Children's Hospital, No. 39 Wangjiang East Road, Wuhu Road Subdistrict, Hefei, Anhui 230051, China
| | - Zhilin Xu
- Department of Pediatric Surgery, The First Affiliated Hospital of Harbin Medical University, No. 199 Dazhi Street, Nangang district, Harbin, Heilongjiang 150001, China
| | - Dianming Wu
- Department of Pediatric Surgery, Fujian Maternity and Child Health Hospital, Fujian Medical University, No. 18 Daoshan Road, Gulou District, Fuzhou, Fujian 350001, China
| | - Donghai Yu
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Xiaojuan Wu
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Jixin Yang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
| | - Bo Xiong
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, No. 13 Hangkong Road, Qiaokou District, Wuhan, Hubei 430030, China
| | - Feng Chen
- Department of Pediatric Surgery, Union Hospital, Fujian Medical University, No. 29, Xinquan Road, Gulou District, Fuzhou, Fujian 350001, China
| | - Xingjie Hao
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College Huazhong University of Science and Technology, No. 13 Hangkong Road, Qiaokou District, Wuhan, Hubei 430030, China
| | - Jiexiong Feng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
- Hubei Clinical Center of Hirschsprung's disease and allied disorders, No. 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei 430030, China
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8
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Kostina A, Kiselev A, Huang A, Lankerd H, Caywood S, Jurado-Fernandez A, Volmert B, O'Hern C, Juhong A, Liu Y, Qiu Z, Park S, Aguirre A. Self-organizing human heart assembloids with autologous and developmentally relevant cardiac neural crest-derived tissues. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.11.627627. [PMID: 39713343 PMCID: PMC11661279 DOI: 10.1101/2024.12.11.627627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Neural crest cells (NCCs) are a multipotent embryonic cell population of ectodermal origin that extensively migrate during early development and contribute to the formation of multiple tissues. Cardiac NCCs play a critical role in heart development by orchestrating outflow tract septation, valve formation, aortic arch artery patterning, parasympathetic innervation, and maturation of the cardiac conduction system. Abnormal migration, proliferation, or differentiation of cardiac NCCs can lead to severe congenital cardiovascular malformations. However, the complexity and timing of early embryonic heart development pose significant challenges to studying the molecular mechanisms underlying NCC-related cardiac pathologies. Here, we present a sophisticated functional model of human heart assembloids derived from induced pluripotent stem cells, which, for the first time, recapitulates cardiac NCC integration into the human embryonic heart in vitro . NCCs successfully integrated at developmentally relevant stages into heart organoids, and followed developmental trajectories known to occur in the human heart. They demonstrated extensive migration, differentiated into cholinergic neurons capable of generating nerve impulses, and formed mature glial cells. Additionally, they contributed to the mesenchymal populations of the developing outflow tract. Through transcriptomic analysis, we revealed that NCCs acquire molecular features of their cardiac derivatives as heart assembloids develop. NCC-derived parasympathetic neurons formed functional connections with cardiomyocytes, promoting the maturation of the cardiac conduction system. Leveraging this model's cellular complexity and functional maturity, we uncovered that early exposure of NCCs to antidepressants harms the development of NCC derivatives in the context of the developing heart. The commonly prescribed antidepressant Paroxetine disrupted the expression of a critical early neuronal transcription factor, resulting in impaired parasympathetic innervation and functional deficits in cardiac tissue. This advanced heart assembloid model holds great promise for high-throughput drug screening and unraveling the molecular mechanisms underlying NCC-related cardiac formation and congenital heart defects. IN BRIEF Human neural crest heart assembloids resembling the major directions of neural crest differentiation in the human embryonic heart, including parasympathetic innervation and the mesenchymal component of the outflow tract, provide a human-relevant embryonic platform for studying congenital heart defects and drug safety.
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9
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Poltavski DM, Cunha AT, Tan J, Sucov HM, Makita T. Lineage-specific intersection of endothelin and GDNF signaling in enteric nervous system development. eLife 2024; 13:RP96424. [PMID: 39641974 PMCID: PMC11623925 DOI: 10.7554/elife.96424] [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] [Indexed: 12/07/2024] Open
Abstract
Two major ligand-receptor signaling axes - endothelin Edn3 and its receptor Ednrb, and glial-derived neurotrophic factor (GDNF) and its receptor Ret - are required for migration of enteric nervous system (ENS) progenitors to the hindgut. Mutations in either component cause colonic aganglionosis, also called Hirschsprung disease. Here, we have used Wnt1Cre and Pax2Cre in mice to show that these driver lines label distinct ENS lineages during progenitor migration and in their terminal hindgut fates. Both Cre lines result in Hirschsprung disease when combined with conditional Ednrb or conditional Ret alleles. In vitro explant assays and analysis of lineage-labeled mutant embryos show that GDNF but not Edn3 is a migration cue for cells of both lineages. Instead, Edn3-Ednrb function is required in both for GDNF responsiveness albeit in different ways: by expanding the Ret+ population in the Pax2Cre lineage, and by supporting Ret function in Wnt1Cre-derived cells. Our results demonstrate that two distinct lineages of progenitors give rise to the ENS, and that these divergently utilize endothelin signaling to support migration to the hindgut.
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Affiliation(s)
- Denise M Poltavski
- Department of Regenerative Medicine and Cell Biology, Medical University of South CarolinaCharlestonUnited States
| | - Alexander T Cunha
- Department of Regenerative Medicine and Cell Biology, Medical University of South CarolinaCharlestonUnited States
| | - Jaime Tan
- Department of Regenerative Medicine and Cell Biology, Medical University of South CarolinaCharlestonUnited States
| | - Henry M Sucov
- Department of Regenerative Medicine and Cell Biology, Medical University of South CarolinaCharlestonUnited States
| | - Takako Makita
- Department of Regenerative Medicine and Cell Biology, Medical University of South CarolinaCharlestonUnited States
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10
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Burns AJ, Goldstein AM. Causes and consequences: development and pathophysiology of Hirschsprung disease. WORLD JOURNAL OF PEDIATRIC SURGERY 2024; 7:e000903. [PMID: 39600627 PMCID: PMC11590806 DOI: 10.1136/wjps-2024-000903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 10/29/2024] [Indexed: 11/29/2024] Open
Abstract
Hirschsprung disease (HSCR) is a congenital enteric neuropathy in which the enteric nervous system (ENS) fails to develop along variable lengths of the distal gastrointestinal (GI) tract. This aganglionosis results in a functional bowel obstruction and requires surgical resection of the aganglionic segment. Despite surgery, however, long-term bowel dysfunction affects many patients. Understanding the embryologic causes and pathophysiologic consequences of HSCR is critical to improving its diagnosis and treatment. During normal gut development, the ENS arises from neural crest cells (NCCs) that delaminate from the neural tube to populate the entire GI tract with enteric neurons and glia. This process requires NCCs to undergo proliferation, migration and differentiation to form the complex neuroglial network that regulates gut motility and other intestinal functions. This review discusses the cellular and molecular processes that control normal ENS formation and what goes awry to give rise to HSCR. The complex pathophysiologic consequences of aganglionosis are discussed, including recent observations that describe novel aspects of HSCR beyond the absence of ganglion cells. This review aims to expand the understanding of HSCR and to stimulate new ideas on how to improve current management of the disease.
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Affiliation(s)
- Alan J Burns
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Allan M Goldstein
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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11
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Zhang HL, Qiu XX, Liao XH. Dermal Papilla Cells: From Basic Research to Translational Applications. BIOLOGY 2024; 13:842. [PMID: 39452150 PMCID: PMC11504027 DOI: 10.3390/biology13100842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/13/2024] [Accepted: 10/18/2024] [Indexed: 10/26/2024]
Abstract
As an appendage of the skin, hair protects against ultraviolet radiation and mechanical damage and regulates body temperature. It also reflects an individual's health status and serves as an important method of expressing personality. Hair loss and graying are significant psychosocial burdens for many people. Hair is produced from hair follicles, which are exclusively controlled by the dermal papilla (DP) at their base. The dermal papilla cells (DPCs) comprise a cluster of specialized mesenchymal cells that induce the formation of hair follicles during early embryonic development through interaction with epithelial precursor cells. They continue to regulate the growth cycle, color, size, and type of hair after the hair follicle matures by secreting various factors. DPCs possess stem cell characteristics and can be cultured and expanded in vitro. DPCs express numerous stemness-related factors, enabling them to be reprogrammed into induced pluripotent stem cells (iPSCs) using only two, or even one, Yamanaka factor. DPCs are an important source of skin-derived precursors (SKPs). When combined with epithelial stem cells, they can reconstitute skin and hair follicles, participating in the regeneration of the dermis, including the DP and dermal sheath. When implanted between the epidermis and dermis, DPCs can induce the formation of new hair follicles on hairless skin. Subcutaneous injection of DPCs and their exosomes can promote hair growth. This review summarizes the in vivo functions of the DP; highlights the potential of DPCs in cell therapy, particularly for the treatment of hair loss; and discusses the challenges and recent advances in the field, from basic research to translational applications.
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Affiliation(s)
- He-Li Zhang
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China;
- School of Life Sciences, Shanghai University, Shanghai 200444, China;
| | - Xi-Xi Qiu
- School of Life Sciences, Shanghai University, Shanghai 200444, China;
| | - Xin-Hua Liao
- School of Life Sciences, Shanghai University, Shanghai 200444, China;
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12
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Wang CH, Tsuji T, Wu LH, Yang CY, Huang TL, Sato M, Shamsi F, Tseng YH. Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue. Nat Commun 2024; 15:7215. [PMID: 39174539 PMCID: PMC11341701 DOI: 10.1038/s41467-024-51579-0] [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: 07/03/2023] [Accepted: 08/12/2024] [Indexed: 08/24/2024] Open
Abstract
Thermogenic adipose tissue, consisting of brown and beige fat, regulates nutrient utilization and energy metabolism. Human brown fat is relatively scarce and decreases with obesity and aging. Hence, inducing thermogenic differentiation of white fat offers an attractive way to enhance whole-body metabolic capacity. Here, we show the role of endothelin 3 (EDN3) and endothelin receptor type B (EDNRB) in promoting the browning of white adipose tissue (WAT). EDNRB overexpression stimulates thermogenic differentiation of human white preadipocytes through cAMP-EPAC1-ERK activation. In mice, cold induces the expression of EDN3 and EDNRB in WAT. Deletion of EDNRB in adipose progenitor cells impairs cold-induced beige adipocyte formation in WAT, leading to excessive weight gain, glucose intolerance, and insulin resistance upon high-fat feeding. Injection of EDN3 into WAT promotes browning and improved whole-body glucose metabolism. The findings shed light on the mechanism of WAT browning and offer potential therapeutics for obesity and metabolic disorders.
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Affiliation(s)
- Chih-Hao Wang
- Graduate Institute of Cell Biology, China Medical University, Taichung City, Taiwan.
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung City, Taiwan.
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
| | - Tadataka Tsuji
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Li-Hong Wu
- Graduate Institute of Cell Biology, China Medical University, Taichung City, Taiwan
| | - Cheng-Ying Yang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung City, Taiwan
| | - Tian Lian Huang
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Mari Sato
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Farnaz Shamsi
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, USA
| | - Yu-Hua Tseng
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
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13
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Sigurðardóttir H, Ablondi M, Kristjansson T, Lindgren G, Eriksson S. Genetic diversity and signatures of selection in Icelandic horses and Exmoor ponies. BMC Genomics 2024; 25:772. [PMID: 39118059 PMCID: PMC11308356 DOI: 10.1186/s12864-024-10682-8] [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: 03/27/2024] [Accepted: 08/01/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND The Icelandic horse and Exmoor pony are ancient, native breeds, adapted to harsh environmental conditions and they have both undergone severe historic bottlenecks. However, in modern days, the selection pressures on these breeds differ substantially. The aim of this study was to assess genetic diversity in both breeds through expected (HE) and observed heterozygosity (HO) and effective population size (Ne). Furthermore, we aimed to identify runs of homozygosity (ROH) to estimate and compare genomic inbreeding and signatures of selection in the breeds. RESULTS HO was estimated at 0.34 and 0.33 in the Icelandic horse and Exmoor pony, respectively, aligning closely with HE of 0.34 for both breeds. Based on genomic data, the Ne for the last generation was calculated to be 125 individuals for Icelandic horses and 42 for Exmoor ponies. Genomic inbreeding coefficient (FROH) ranged from 0.08 to 0.20 for the Icelandic horse and 0.12 to 0.27 for the Exmoor pony, with the majority of inbreeding attributed to short ROHs in both breeds. Several ROH islands associated with performance were identified in the Icelandic horse, featuring target genes such as DMRT3, DOCK8, EDNRB, SLAIN1, and NEURL1. Shared ROH islands between both breeds were linked to metabolic processes (FOXO1), body size, and the immune system (CYRIB), while private ROH islands in Exmoor ponies were associated with coat colours (ASIP, TBX3, OCA2), immune system (LYG1, LYG2), and fertility (TEX14, SPO11, ADAM20). CONCLUSIONS Evaluations of genetic diversity and inbreeding reveal insights into the evolutionary trajectories of both breeds, highlighting the consequences of population bottlenecks. While the genetic diversity in the Icelandic horse is acceptable, a critically low genetic diversity was estimated for the Exmoor pony, which requires further validation. Identified signatures of selection highlight the differences in the use of the two breeds as well as their adaptive trait similarities. The results provide insight into genomic regions under selection pressure in a gaited performance horse breed and various adaptive traits in small-sized native horse breeds. This understanding contributes to preserving genetic diversity and population health in these equine populations.
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Affiliation(s)
- Heiðrún Sigurðardóttir
- Department of Animal Biosciences, Swedish University of Agricultural Sciences, P.O. Box 7023, Uppsala, 75007, Sweden.
- Faculty of Agricultural Sciences, Agricultural University of Iceland, Hvanneyri, Borgarbyggð, 311, Iceland.
| | - Michela Ablondi
- Department of Veterinary Science, University of Parma, Parma, 43126, Italy
| | - Thorvaldur Kristjansson
- Faculty of Agricultural Sciences, Agricultural University of Iceland, Hvanneyri, Borgarbyggð, 311, Iceland
| | - Gabriella Lindgren
- Department of Animal Biosciences, Swedish University of Agricultural Sciences, P.O. Box 7023, Uppsala, 75007, Sweden
- Center for Animal Breeding and Genetics, Department of Biosystems, KU Leuven, Leuven, 3001, Belgium
| | - Susanne Eriksson
- Department of Animal Biosciences, Swedish University of Agricultural Sciences, P.O. Box 7023, Uppsala, 75007, Sweden
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14
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Dai D, Sari EM, Si J, Ashari H, Dagong MIA, Pauciullo A, Lenstra JA, Han J, Zhang Y. Genomic analysis reveals the association of KIT and MITF variants with the white spotting in swamp buffaloes. BMC Genomics 2024; 25:713. [PMID: 39048931 PMCID: PMC11267946 DOI: 10.1186/s12864-024-10634-2] [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: 02/24/2024] [Accepted: 07/18/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Swamp-type buffaloes with varying degrees of white spotting are found exclusively in Tana Toraja, South Sulawesi, Indonesia, where spotted buffalo bulls are highly valued in accordance with the Torajan customs. The white spotting depigmentation is caused by the absence of melanocytes. However, the genetic variants that cause this phenotype have not been fully characterized. The objective of this study was to identify the genomic regions and variants responsible for this unique coat-color pattern. RESULTS Genome-wide association study (GWAS) and selection signature analysis identified MITF as a key gene based on the whole-genome sequencing data of 28 solid and 39 spotted buffaloes, while KIT was also found to be involved in the development of this phenotype by a candidate gene approach. Alternative candidate mutations included, in addition to the previously reported nonsense mutation c.649 C > T (p.Arg217*) and splice donor mutation c.1179 + 2T > A in MITF, a nonsense mutation c.2028T > A (p.Tyr676*) in KIT. All these three mutations were located in the genomic regions that were highly conserved exclusively in Indonesian swamp buffaloes and they accounted largely (95%) for the manifestation of white spotting. Last but not the least, ADAMTS20 and TWIST2 may also contribute to the diversification of this coat-color pattern. CONCLUSIONS The alternative mutations identified in this study affect, at least partially and independently, the development of melanocytes. The presence and persistence of such mutations may be explained by significant financial and social value of spotted buffaloes used in historical Rambu Solo ceremony in Tana Toraja, Indonesia. Several de novo spontaneous mutations have therefore been favored by traditional breeding for the spotted buffaloes.
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Affiliation(s)
- Dongmei Dai
- State Key Laboratory of Animal Biotech Breeding, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Eka Meutia Sari
- Department of Animal Science, Agriculture Faculty, Universitas Syiah Kuala (USK), Banda Aceh, 23111, Indonesia.
| | - Jingfang Si
- State Key Laboratory of Animal Biotech Breeding, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Hidayat Ashari
- Research Center for Biosystematics and Evolution, National Research and Innovation Agency (BRIN), Cibinong, 16911, Indonesia
| | - Muhammad Ihsan Andi Dagong
- Animal Production Department, Faculty of Animal Science, Hasanuddin University, Makassar, 90245, Indonesia
| | - Alfredo Pauciullo
- Department of Agricultural, Forest and Food Sciences, University of Turin, Grugliasco (TO), 10095, Italy
| | - Johannes A Lenstra
- Faculty of Veterinary Medicine, Utrecht University, Yalelaan 104, 3584 CM, Utrecht, The Netherlands
| | - Jianlin Han
- Yazhouwan National Laboratory, Sanya, 572024, China
| | - Yi Zhang
- State Key Laboratory of Animal Biotech Breeding, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
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15
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Tai Y, Han D, Yang X, Cai G, Li H, Li J, Deng X. Endothelin-3 Suppresses Luteinizing Hormone Receptor Expression by Regulating the cAMP-PKA Pathway in Hen Granulosa Cells. Curr Issues Mol Biol 2024; 46:7832-7845. [PMID: 39194681 DOI: 10.3390/cimb46080464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 08/29/2024] Open
Abstract
Previous research identified the expression of EDN3 in granulosa cells of preovulatory follicles in chickens. Notably, the expression level of EDN3 in Silky Fowl with low egg-laying performance was significantly higher than that in high-yield laying breed White Leghorn. Given the crucial role of granulosa cells in follicular development and maturation, it is very important to study the effect of EDN3 on the biological function of granular cells. In this study, an EDN3 overexpression plasmid was constructed and transfected into granular cells. The viability of these cells was detected using quantiative (qPCR), Cell Counting Kit-8 (CCK8), and 5-Ethynyl-2'-deoxyuridine (EdU) assays. Gonadal hormone synthesis was detected using enzyme-linked immunosorbent assay (ELISA) techniques. Finally, transcriptome sequencing was employed to identify differentially expressed genes. Result showed thatoverexpression of EDN3 was observed to promote cell viability. In addition, it significantly inhibits the expressions of LHR and cAMP-PKA signaling pathways. Cell transcriptome sequencing data displayed that EDN3 can upregulate energy metabolism and immune-related signaling pathways, whereas follicle maturation and the GnRH signaling pathway were downregulated. In conclusion, this study demonstrates that EDN3 can enhance granulosa cell viability and inhibit the expression of LHCGR, a process likely mediated through the cAMP-PKA signaling pathway. However, further evidence is required to substantiate the regulatory relationship between EDN3 and the cAMP-PKA signaling pathway.
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Affiliation(s)
- Yurong Tai
- Sanya Institute, China Agricultural University, Sanya, 572000, China
- Hainan Seed Industry Laboratory, Yazhou 572024, China
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory For Animal Breeding, China Agricultural University, Beijing 100000, China
| | - Deping Han
- Sanya Institute, China Agricultural University, Sanya, 572000, China
| | - Xue Yang
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory For Animal Breeding, China Agricultural University, Beijing 100000, China
| | - Ganxian Cai
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory For Animal Breeding, China Agricultural University, Beijing 100000, China
| | - Huaiyu Li
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory For Animal Breeding, China Agricultural University, Beijing 100000, China
| | - Junying Li
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory For Animal Breeding, China Agricultural University, Beijing 100000, China
| | - Xuemei Deng
- Sanya Institute, China Agricultural University, Sanya, 572000, China
- Hainan Seed Industry Laboratory, Yazhou 572024, China
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory For Animal Breeding, China Agricultural University, Beijing 100000, China
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16
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Fegraeus K, Rosengren MK, Naboulsi R, Orlando L, Åbrink M, Jouni A, Velie BD, Raine A, Egner B, Mattsson CM, Lång K, Zhigulev A, Björck HM, Franco-Cereceda A, Eriksson P, Andersson G, Sahlén P, Meadows JRS, Lindgren G. An endothelial regulatory module links blood pressure regulation with elite athletic performance. PLoS Genet 2024; 20:e1011285. [PMID: 38885195 PMCID: PMC11182536 DOI: 10.1371/journal.pgen.1011285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 05/02/2024] [Indexed: 06/20/2024] Open
Abstract
The control of transcription is crucial for homeostasis in mammals. A previous selective sweep analysis of horse racing performance revealed a 19.6 kb candidate regulatory region 50 kb downstream of the Endothelin3 (EDN3) gene. Here, the region was narrowed to a 5.5 kb span of 14 SNVs, with elite and sub-elite haplotypes analyzed for association to racing performance, blood pressure and plasma levels of EDN3 in Coldblooded trotters and Standardbreds. Comparative analysis of human HiCap data identified the span as an enhancer cluster active in endothelial cells, interacting with genes relevant to blood pressure regulation. Coldblooded trotters with the sub-elite haplotype had significantly higher blood pressure compared to horses with the elite performing haplotype during exercise. Alleles within the elite haplotype were part of the standing variation in pre-domestication horses, and have risen in frequency during the era of breed development and selection. These results advance our understanding of the molecular genetics of athletic performance and vascular traits in both horses and humans.
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Affiliation(s)
- Kim Fegraeus
- Department of Medical Sciences, Science for life laboratory, Uppsala University, Sweden
| | - Maria K. Rosengren
- Department of Animal Biosciences, Swedish University of Agricultural Sciences Uppsala, Sweden
| | - Rakan Naboulsi
- Department of Animal Biosciences, Swedish University of Agricultural Sciences Uppsala, Sweden
- Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institute, Stockholm
| | - Ludovic Orlando
- Centre d’Anthropobiologie et de Génomique de Toulouse (CNRS UMR 5288), Université Paul Sabatier, Toulouse, France
| | - Magnus Åbrink
- Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Ahmad Jouni
- Department of Animal Biosciences, Swedish University of Agricultural Sciences Uppsala, Sweden
| | - Brandon D. Velie
- School of Life & Environmental Sciences, University of Sydney, Sydney, Australia
| | - Amanda Raine
- Department of Medical Sciences, Science for life laboratory, Uppsala University, Sweden
| | - Beate Egner
- Department of Cardio-Vascular Research, Veterinary Academy of Higher Learning, Babenhausen, Germany
| | - C Mikael Mattsson
- Silicon Valley Exercise Analytics (svexa), MenloPark, CA, United States of America
| | - Karin Lång
- Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Karolinska University Hospital, Solna, Sweden
| | - Artemy Zhigulev
- KTH Royal Institute of Technology, School of Chemistry, Biotechnology and Health, Science for Life Laboratory, Stockholm, Sweden
| | - Hanna M. Björck
- Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Karolinska University Hospital, Solna, Sweden
| | - Anders Franco-Cereceda
- Section of Cardiothoracic Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Per Eriksson
- Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Karolinska University Hospital, Solna, Sweden
| | - Göran Andersson
- Department of Animal Biosciences, Swedish University of Agricultural Sciences Uppsala, Sweden
| | - Pelin Sahlén
- KTH Royal Institute of Technology, School of Chemistry, Biotechnology and Health, Science for Life Laboratory, Stockholm, Sweden
| | - Jennifer R. S. Meadows
- Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Gabriella Lindgren
- Department of Animal Biosciences, Swedish University of Agricultural Sciences Uppsala, Sweden
- Center for Animal Breeding and Genetics, Department of Biosystems, KU Leuven, Leuven, Belgium
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17
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Kanai SM, Clouthier DE. Endothelin signaling in development. Development 2023; 150:dev201786. [PMID: 38078652 PMCID: PMC10753589 DOI: 10.1242/dev.201786] [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] [Indexed: 12/18/2023]
Abstract
Since the discovery of endothelin 1 (EDN1) in 1988, the role of endothelin ligands and their receptors in the regulation of blood pressure in normal and disease states has been extensively studied. However, endothelin signaling also plays crucial roles in the development of neural crest cell-derived tissues. Mechanisms of endothelin action during neural crest cell maturation have been deciphered using a variety of in vivo and in vitro approaches, with these studies elucidating the basis of human syndromes involving developmental differences resulting from altered endothelin signaling. In this Review, we describe the endothelin pathway and its functions during the development of neural crest-derived tissues. We also summarize how dysregulated endothelin signaling causes developmental differences and how this knowledge may lead to potential treatments for individuals with gene variants in the endothelin pathway.
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Affiliation(s)
- Stanley M. Kanai
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - David E. Clouthier
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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18
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Jacobs-Li J, Tang W, Li C, Bronner ME. Single-cell profiling coupled with lineage analysis reveals vagal and sacral neural crest contributions to the developing enteric nervous system. eLife 2023; 12:e79156. [PMID: 37877560 PMCID: PMC10627514 DOI: 10.7554/elife.79156] [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: 04/01/2022] [Accepted: 10/23/2023] [Indexed: 10/26/2023] Open
Abstract
During development, much of the enteric nervous system (ENS) arises from the vagal neural crest that emerges from the caudal hindbrain and colonizes the entire gastrointestinal tract. However, a second ENS contribution comes from the sacral neural crest that arises in the caudal neural tube and populates the post-umbilical gut. By coupling single-cell transcriptomics with axial-level-specific lineage tracing in avian embryos, we compared the contributions of embryonic vagal and sacral neural crest cells to the chick ENS and the associated peripheral ganglia (Nerve of Remak and pelvic plexuses). At embryonic day (E) 10, the two neural crest populations form overlapping subsets of neuronal and glia cell types. Surprisingly, the post-umbilical vagal neural crest much more closely resembles the sacral neural crest than the pre-umbilical vagal neural crest. However, some differences in cluster types were noted between vagal and sacral derived cells. Notably, RNA trajectory analysis suggests that the vagal neural crest maintains a neuronal/glial progenitor pool, whereas this cluster is depleted in the E10 sacral neural crest which instead has numerous enteric glia. The present findings reveal sacral neural crest contributions to the hindgut and associated peripheral ganglia and highlight the potential influence of the local environment and/or developmental timing in differentiation of neural crest-derived cells in the developing ENS.
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Affiliation(s)
- Jessica Jacobs-Li
- Division of Biology and Biological Engineering, California Institute of TechnologyPasadenaUnited States
| | - Weiyi Tang
- Division of Biology and Biological Engineering, California Institute of TechnologyPasadenaUnited States
| | - Can Li
- Division of Biology and Biological Engineering, California Institute of TechnologyPasadenaUnited States
| | - Marianne E Bronner
- Division of Biology and Biological Engineering, California Institute of TechnologyPasadenaUnited States
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19
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Dao UM, Lederer I, Tabor RL, Shahid B, Graves CW, Seidel HS. Stripes and loss of color in ball pythons (Python regius) are associated with variants affecting endothelin signaling. G3 (BETHESDA, MD.) 2023; 13:jkad063. [PMID: 37191439 PMCID: PMC10320763 DOI: 10.1093/g3journal/jkad063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 03/10/2023] [Indexed: 05/17/2023]
Abstract
Color patterns in nonavian reptiles are beautifully diverse, but little is known about the genetics and development of these patterns. Here, we investigated color patterning in pet ball pythons (Python regius), which have been bred to show color phenotypes that differ dramatically from the wildtype form. We report that several color phenotypes in pet animals are associated with putative loss-of-function variants in the gene encoding endothelin receptor EDNRB1: (1) frameshift variants in EDNRB1 are associated with conversion of the normal mottled color pattern to skin that is almost fully white, (2) missense variants affecting conserved sites of the EDNRB1 protein are associated with dorsal, longitudinal stripes, and (3) substitutions at EDNRB1 splice donors are associated with subtle changes in patterning compared to wildtype. We propose that these phenotypes are caused by loss of specialized color cells (chromatophores), with loss ranging from severe (fully white) to moderate (dorsal striping) to mild (subtle changes in patterning). Our study is the first to describe variants affecting endothelin signaling in a nonavian reptile and suggests that reductions in endothelin signaling in ball pythons can produce a variety of color phenotypes, depending on the degree of color cell loss.
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Affiliation(s)
- Uyen M Dao
- Department of Biology, Eastern Michigan University, Ypsilanti, MI 48197, USA
| | - Izabella Lederer
- Department of Biology, Eastern Michigan University, Ypsilanti, MI 48197, USA
| | - Ray L Tabor
- Department of Biology, Eastern Michigan University, Ypsilanti, MI 48197, USA
| | - Basmah Shahid
- Department of Biology, Eastern Michigan University, Ypsilanti, MI 48197, USA
| | - Chiron W Graves
- Department of Biology, Eastern Michigan University, Ypsilanti, MI 48197, USA
| | - Hannah S Seidel
- Department of Biology, Eastern Michigan University, Ypsilanti, MI 48197, USA
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20
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Fernandes B, Cavaco-Paulo A, Matamá T. A Comprehensive Review of Mammalian Pigmentation: Paving the Way for Innovative Hair Colour-Changing Cosmetics. BIOLOGY 2023; 12:biology12020290. [PMID: 36829566 PMCID: PMC9953601 DOI: 10.3390/biology12020290] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/26/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023]
Abstract
The natural colour of hair shafts is formed at the bulb of hair follicles, and it is coupled to the hair growth cycle. Three critical processes must happen for efficient pigmentation: (1) melanosome biogenesis in neural crest-derived melanocytes, (2) the biochemical synthesis of melanins (melanogenesis) inside melanosomes, and (3) the transfer of melanin granules to surrounding pre-cortical keratinocytes for their incorporation into nascent hair fibres. All these steps are under complex genetic control. The array of natural hair colour shades are ascribed to polymorphisms in several pigmentary genes. A myriad of factors acting via autocrine, paracrine, and endocrine mechanisms also contributes for hair colour diversity. Given the enormous social and cosmetic importance attributed to hair colour, hair dyeing is today a common practice. Nonetheless, the adverse effects of the long-term usage of such cosmetic procedures demand the development of new methods for colour change. In this context, case reports of hair lightening, darkening and repigmentation as a side-effect of the therapeutic usage of many drugs substantiate the possibility to tune hair colour by interfering with the biology of follicular pigmentary units. By scrutinizing mammalian pigmentation, this review pinpoints key targetable processes for the development of innovative cosmetics that can safely change the hair colour from the inside out.
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Affiliation(s)
- Bruno Fernandes
- CEB—Centre of Biological Engineering, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
| | - Artur Cavaco-Paulo
- CEB—Centre of Biological Engineering, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
- LABBELS—Associate Laboratory, 4710-057 Braga, Portugal
- Correspondence: (A.C.-P.); (T.M.); Tel.: +351-253-604-409 (A.C.-P.); +351-253-601-599 (T.M.)
| | - Teresa Matamá
- CEB—Centre of Biological Engineering, University of Minho, Campus of Gualtar, 4710-057 Braga, Portugal
- LABBELS—Associate Laboratory, 4710-057 Braga, Portugal
- Correspondence: (A.C.-P.); (T.M.); Tel.: +351-253-604-409 (A.C.-P.); +351-253-601-599 (T.M.)
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21
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Dai M, Zhou N, Zhang Y, Zhang Y, Ni K, Wu Z, Liu L, Wang X, Chen Q. Genome-wide analysis of the SBT gene family involved in drought tolerance in cotton. FRONTIERS IN PLANT SCIENCE 2023; 13:1097732. [PMID: 36714777 PMCID: PMC9875013 DOI: 10.3389/fpls.2022.1097732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 12/12/2022] [Indexed: 06/18/2023]
Abstract
The subtilisin-like proteases (SBTs) are a large family of serine peptidases that are unique to plants. Previous studies have shown that SBTs are associated with developmental processes and environmental responses. However, comprehensive identification and systematic analysis of the SBT family have not been conducted in cotton. We used bioinformatics methods to analyze the structural characteristics, phylogenetic relationships, gene structures, expression modes, evolutionary relationships, selection pressures and stress responses of SBT gene family members in upland cotton. In this study, we identified 120 and 112 SBTs in the tetraploid cotton species G. hirsutum and G. barbadense, while 67 and 69 SBTs were identified in the diploid species G. arboreum and G. raimondii, respectively; these SBTs were divided into five distinct subfamilies. We identified the SBT gene GhSBT27A, and explore its function through virus-induced gene silencing and transmission electron microscopy. These results suggested that the GhSBT27A gene was involved in the response to drought stress. These results lay a foundation for further study on the drought stress mechanism of cotton.
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Affiliation(s)
- Maohua Dai
- Engineering Research Centre of Cotton, Ministry of Education/College of Agriculture, Xinjiang Agricultural University, Urumqi, China
- Dryland Farming Institute, Hebei Academy of Agricultural and Forestry Sciences/Hebei Key Laboratory of Crops Drought Resistance, Hengshui, China
| | - Na Zhou
- Dryland Farming Institute, Hebei Academy of Agricultural and Forestry Sciences/Hebei Key Laboratory of Crops Drought Resistance, Hengshui, China
| | - Yue Zhang
- Dryland Farming Institute, Hebei Academy of Agricultural and Forestry Sciences/Hebei Key Laboratory of Crops Drought Resistance, Hengshui, China
| | - Yuexin Zhang
- Dryland Farming Institute, Hebei Academy of Agricultural and Forestry Sciences/Hebei Key Laboratory of Crops Drought Resistance, Hengshui, China
| | - Kesong Ni
- Engineering Research Centre of Cotton, Ministry of Education/College of Agriculture, Xinjiang Agricultural University, Urumqi, China
| | - Zhenliang Wu
- Dryland Farming Institute, Hebei Academy of Agricultural and Forestry Sciences/Hebei Key Laboratory of Crops Drought Resistance, Hengshui, China
| | - Liying Liu
- Dryland Farming Institute, Hebei Academy of Agricultural and Forestry Sciences/Hebei Key Laboratory of Crops Drought Resistance, Hengshui, China
| | - Xiaoge Wang
- Institute of Industrial Crops, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Quanjia Chen
- Engineering Research Centre of Cotton, Ministry of Education/College of Agriculture, Xinjiang Agricultural University, Urumqi, China
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22
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Zhang Z, Li B, Jiang Q, Li Q, Pierro A, Li L. Hirschsprung-Associated Enterocolitis: Transformative Research from Bench to Bedside. Eur J Pediatr Surg 2022; 32:383-390. [PMID: 35649434 DOI: 10.1055/s-0042-1745780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Hirschsprung disease (HSCR) is a congenital disease that is characterized by the absence of intrinsic ganglion cells in the submucosal and myenteric plexuses of the distal colon and is the most common cause of congenital intestinal obstruction. Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of HSCR, which can occur either before or after surgical resection of the aganglionic bowel. Even though HAEC is a leading cause of death in HSCR patients, its etiology and pathophysiology remain poorly understood. Various factors have been associated with HAEC, including the mucus barrier, microbiota, immune function, obstruction of the colon, and genetic variations. In this review, we examine our current mouse model of HAEC and how it informs our understanding of the disease. We also describe current emerging research that highlights the potential future of HAEC treatment.
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Affiliation(s)
- Zhen Zhang
- Department of General Surgery, Capital Institute of Pediatrics, Beijing, Beijing, China
| | - Bo Li
- Translational Medicine Program, Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Qian Jiang
- Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China
| | - Qi Li
- Department of General Surgery, Capital Institute of Pediatrics, Beijing, Beijing, China
| | - Agostino Pierro
- Department of Paediatric Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Long Li
- Department of General Surgery, Capital Institute of Pediatrics, Beijing, Beijing, China
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23
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Kastriti ME, Faure L, Von Ahsen D, Bouderlique TG, Boström J, Solovieva T, Jackson C, Bronner M, Meijer D, Hadjab S, Lallemend F, Erickson A, Kaucka M, Dyachuk V, Perlmann T, Lahti L, Krivanek J, Brunet J, Fried K, Adameyko I. Schwann cell precursors represent a neural crest-like state with biased multipotency. EMBO J 2022; 41:e108780. [PMID: 35815410 PMCID: PMC9434083 DOI: 10.15252/embj.2021108780] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 06/14/2022] [Accepted: 06/15/2022] [Indexed: 12/29/2022] Open
Abstract
Schwann cell precursors (SCPs) are nerve-associated progenitors that can generate myelinating and non-myelinating Schwann cells but also are multipotent like the neural crest cells from which they originate. SCPs are omnipresent along outgrowing peripheral nerves throughout the body of vertebrate embryos. By using single-cell transcriptomics to generate a gene expression atlas of the entire neural crest lineage, we show that early SCPs and late migratory crest cells have similar transcriptional profiles characterised by a multipotent "hub" state containing cells biased towards traditional neural crest fates. SCPs keep diverging from the neural crest after being primed towards terminal Schwann cells and other fates, with different subtypes residing in distinct anatomical locations. Functional experiments using CRISPR-Cas9 loss-of-function further show that knockout of the common "hub" gene Sox8 causes defects in neural crest-derived cells along peripheral nerves by facilitating differentiation of SCPs towards sympathoadrenal fates. Finally, specific tumour populations found in melanoma, neurofibroma and neuroblastoma map to different stages of SCP/Schwann cell development. Overall, SCPs resemble migrating neural crest cells that maintain multipotency and become transcriptionally primed towards distinct lineages.
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Affiliation(s)
- Maria Eleni Kastriti
- Department of Molecular Neuroscience, Center for Brain ResearchMedical University ViennaViennaAustria
- Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden
- Department of Neuroimmunology, Center for Brain ResearchMedical University ViennaViennaAustria
| | - Louis Faure
- Department of Neuroimmunology, Center for Brain ResearchMedical University ViennaViennaAustria
| | - Dorothea Von Ahsen
- Department of Neuroimmunology, Center for Brain ResearchMedical University ViennaViennaAustria
| | | | - Johan Boström
- Department of Neuroimmunology, Center for Brain ResearchMedical University ViennaViennaAustria
| | - Tatiana Solovieva
- Division of Biology and Biological EngineeringCalifornia Institute of TechnologyPasadenaCAUSA
| | - Cameron Jackson
- Division of Biology and Biological EngineeringCalifornia Institute of TechnologyPasadenaCAUSA
| | - Marianne Bronner
- Division of Biology and Biological EngineeringCalifornia Institute of TechnologyPasadenaCAUSA
| | - Dies Meijer
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
| | - Saida Hadjab
- Department of NeuroscienceKarolinska InstitutetStockholmSweden
| | | | - Alek Erickson
- Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden
| | - Marketa Kaucka
- Max Planck Institute for Evolutionary BiologyPlönGermany
| | | | - Thomas Perlmann
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
| | - Laura Lahti
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
| | - Jan Krivanek
- Department of Histology and Embryology, Faculty of MedicineMasaryk UniversityBrnoCzech Republic
| | - Jean‐Francois Brunet
- Institut de Biologie de l'ENS (IBENS), INSERM, CNRS, École Normale SupérieurePSL Research UniversityParisFrance
| | - Kaj Fried
- Department of NeuroscienceKarolinska InstitutetStockholmSweden
| | - Igor Adameyko
- Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden
- Department of Neuroimmunology, Center for Brain ResearchMedical University ViennaViennaAustria
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24
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Genetic insights, disease mechanisms, and biological therapeutics for Waardenburg syndrome. Gene Ther 2022; 29:479-497. [PMID: 33633356 DOI: 10.1038/s41434-021-00240-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/18/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023]
Abstract
Waardenburg syndrome (WS), also known as auditory-pigmentary syndrome, is the most common cause of syndromic hearing loss (HL), which accounts for approximately 2-5% of all patients with congenital hearing loss. WS is classified into four subtypes depending on the clinical phenotypes. Currently, pathogenic mutations of PAX3, MITF, SOX10, EDN3, EDNRB or SNAI2 are associated with different subtypes of WS. Although supportive techniques like hearing aids, cochlear implants, or other assistive listening devices can alleviate the HL symptom, there is no cure for WS to date. Recently major progress has been achieved in preclinical studies of genetic HL in animal models, including gene delivery and stem cell replacement therapies. This review focuses on the current understandings of pathogenic mechanisms and potential biological therapeutic approaches for HL in WS, providing strategies and directions for implementing WS biological therapies, as well as possible problems to be faced, in the future.
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25
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Chevalier NR. Physical organogenesis of the gut. Development 2022; 149:276365. [DOI: 10.1242/dev.200765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
ABSTRACT
The gut has been a central subject of organogenesis since Caspar Friedrich Wolff’s seminal 1769 work ‘De Formatione Intestinorum’. Today, we are moving from a purely genetic understanding of cell specification to a model in which genetics codes for layers of physical–mechanical and electrical properties that drive organogenesis such that organ function and morphogenesis are deeply intertwined. This Review provides an up-to-date survey of the extrinsic and intrinsic mechanical forces acting on the embryonic vertebrate gut during development and of their role in all aspects of intestinal morphogenesis: enteric nervous system formation, epithelium structuring, muscle orientation and differentiation, anisotropic growth and the development of myogenic and neurogenic motility. I outline numerous implications of this biomechanical perspective in the etiology and treatment of pathologies, such as short bowel syndrome, dysmotility, interstitial cells of Cajal-related disorders and Hirschsprung disease.
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Affiliation(s)
- Nicolas R. Chevalier
- Laboratoire Matière et Systèmes Complexes, Université Paris Cité, CNRS UMR 7057 , 10 rue Alice Domon et Léonie Duquet, 75013 Paris , France
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26
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Jain A, Bozovicar K, Mehrotra V, Bratkovic T, Johnson MH, Jha I. Investigating the specificity of endothelin-traps as a potential therapeutic tool for endothelin-1 related disorders. World J Diabetes 2022; 13:434-441. [PMID: 35800412 PMCID: PMC9210543 DOI: 10.4239/wjd.v13.i6.434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 04/24/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Endothelin (ET)-traps are Fc-fusion proteins with a design based on the physiological receptors of ET-1. Previous work has shown that use of the selected ET-traps potently and significantly reduces different markers of diabetes pathology back to normal, non-disease levels.
AIM To demonstrate the selected ET-traps potently and significantly bind to ET-1.
METHODS We performed phage display experiments to test different constructs of ET-traps, and conducted bio-layer interferometry binding assays to verify that the selected ET-traps bind specifically to ET-1 and display binding affinity in the double-digit picomolar range (an average of 73.8 rM, n = 6).
RESULTS These experiments have confirmed our choice of the final ET-traps and provided proof-of-concept for the potential use of constructs as effective biologics for diseases associated with pathologically elevated ET-1.
CONCLUSION There is increased need for such therapeutics as they could help save millions of lives around the world.
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Affiliation(s)
- Arjun Jain
- ET-Traps Limited, Cambridge CB3 0JE, United Kingdom
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom
- Accelerate Cambridge, Judge Business School, University of Cambridge, Cambridge CB2 1AG, United Kingdom
| | - Kristof Bozovicar
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Slovenia 1000, Slovenia
| | - Vidhi Mehrotra
- ET-Traps Limited, Cambridge CB3 0JE, United Kingdom
- Accelerate Cambridge, Judge Business School, University of Cambridge, Cambridge CB2 1AG, United Kingdom
| | - Tomaz Bratkovic
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Slovenia 1000, Slovenia
| | - Martin H Johnson
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom
| | - Ira Jha
- ET-Traps Limited, Cambridge CB3 0JE, United Kingdom
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27
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Mutations in rhodopsin, endothelin B receptor, and CC chemokine receptor 5 in large animals: Modeling human diseases. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2022; 189:155-178. [PMID: 35595348 DOI: 10.1016/bs.pmbts.2022.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
G protein-coupled receptors (GPCRs) are the largest family of cell membrane receptors involved in modulating almost all physiological processes by transducing extracellular signals into the cytoplasm. Dysfunctions of GPCR-regulated signaling result in diverse human diseases, making GPCRs the most popular drug targets for human medicine. Large animals share higher similarities (in physiology and metabolism) with humans than rodents. Similar to findings in human genetics, diverse diseases caused by mutations in GPCR genes have also been discovered in large animals. Rhodopsin, endothelin B receptor, and CC chemokine receptor type 5 have been shown to be involved in human retinitis pigmentosa, Hirschsprung disease, and HIV infection/AIDS, respectively, and several mutations of these GPCRs have also been identified from large animals. The large animals with naturally occurring mutations of these GPCRs provide an opportunity to gain a better understanding of the pathogenesis of human diseases, and can be used for preclinical trials of therapies for human diseases. In this review, we aim to summarize the naturally occurring mutations of these three GPCRs in large animals and humans.
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28
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Endothelin and the Cardiovascular System: The Long Journey and Where We Are Going. BIOLOGY 2022; 11:biology11050759. [PMID: 35625487 PMCID: PMC9138590 DOI: 10.3390/biology11050759] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/11/2022] [Accepted: 05/12/2022] [Indexed: 12/12/2022]
Abstract
Simple Summary In this review, we describe the basic functions of endothelin and related molecules, including their receptors and enzymes. Furthermore, we discuss the important role of endothelin in several cardiovascular diseases, the relevant clinical evidence for targeting the endothelin pathway, and the scope of endothelin-targeting treatments in the future. We highlight the present uses of endothelin receptor antagonists and the advancements in the development of future treatment options, thereby providing an overview of endothelin research over the years and its future scope. Abstract Endothelin was first discovered more than 30 years ago as a potent vasoconstrictor. In subsequent years, three isoforms, two canonical receptors, and two converting enzymes were identified, and their basic functions were elucidated by numerous preclinical and clinical studies. Over the years, the endothelin system has been found to be critical in the pathogenesis of several cardiovascular diseases, including hypertension, pulmonary arterial hypertension, heart failure, and coronary artery disease. In this review, we summarize the current knowledge on endothelin and its role in cardiovascular diseases. Furthermore, we discuss how endothelin-targeting therapies, such as endothelin receptor antagonists, have been employed to treat cardiovascular diseases with varying degrees of success. Lastly, we provide a glimpse of what could be in store for endothelin-targeting treatment options for cardiovascular diseases in the future.
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29
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Sahut-Barnola I, Lefrancois-Martinez AM, Dufour D, Jean-Marie BOTTO, Kamilaris C, Faucz FR, Stratakis CA, Val P, Martinez A. Steroidogenic factor-1 lineage origin of skin lesions in Carney complex syndrome. J Invest Dermatol 2022; 142:2949-2957.e9. [PMID: 35568059 DOI: 10.1016/j.jid.2022.04.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 03/28/2022] [Accepted: 04/16/2022] [Indexed: 02/02/2023]
Abstract
Carney complex (CNC) is a rare familial multi-neoplastic syndrome predisposing to endocrine and non-endocrine tumors due to inactivating mutations of PRKAR1A leading to perturbations of the cAMP protein kinase A (PKA) signaling pathway. Skin lesions are the most common manifestation of CNC, including lentigines, blue nevi and cutaneous myxomas, in unusual locations such as oral and genital mucosa. Unlike endocrine disorders, the pathogenesis of skin lesions remains unexplained. Here, we show that embryonic invalidation of the Prkar1a gene in Steroidogenic Factor-1-expressing cells, leads to the development of familial skin pigmentation alterations reminiscent of those in patients. Immunohistological and molecular analyses coupled with genetic monitoring of recombinant cell lineages in mouse skin, suggest that familial lentiginosis and myxomas occurs in skin areas specifically enriched in dermal melanocytes. In lentigines and blue nevi-prone areas from mutant mice and patients, Prkar1a/PRKAR1A invalidation occurs in a subset of dermal fibroblasts capable of inducing, under the influence of PKA signaling, the production of pro-melanogenic EDN3 and HGF signals. Our model strongly suggests that the origin of the typical CNC cutaneous lesions is the result of non-cell-autonomous pro-melanogenic activity of a dermal fibroblast population sharing a community of origin with SF-1 lineage.
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Affiliation(s)
| | | | - Damien Dufour
- iGReD, CNRS, Inserm, Université Clermont-Auvergne, France
| | | | | | | | | | - Pierre Val
- iGReD, CNRS, Inserm, Université Clermont-Auvergne, France
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30
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Gao L, Chen EQ, Zhong HB, Xie J, Song HZ, Zhao XB, Lin LR, Liu Q, Wang S, Wu WY, Zhao RC, Liao XH. Large-scale isolation of functional dermal papilla cells using novel surface marker LEPR. Cytometry A 2022; 101:675-681. [PMID: 35524584 DOI: 10.1002/cyto.a.24569] [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: 02/02/2022] [Revised: 03/24/2022] [Accepted: 04/26/2022] [Indexed: 11/12/2022]
Abstract
Dermal papilla (DP) cells regulate hair follicle epithelial cells and melanocytes by secreting functional factors, playing a key role in hair follicle morphogenesis and hair growth. DP cells can reconstitute new hair follicles and induce hair regeneration, providing a potential therapeutic strategy for treating hair loss. However, current methods for isolating DP cells are either inefficient (physical microdissection) or only applied to genetically labeled mice. We systematically screened for the surface proteins specifically expressed in skin DP using mRNA expression databases. We identified two antibodies against receptors LEPR and SCARA5 which could specifically label and isolate DP cells by flow cytometry from mice back skin at the growth phase. The sorted LEPR+ cells maintained the DP characteristics after culturing in vitro, expressing DP marker alkaline phosphatase and functional factors including RSPO1/2 and EDN3, the three major DP secretory factors that regulate hair follicle epithelial cells and melanocytes. Furthermore, the low-passage LEPR+ DP cells could reconstitute hair follicles on nude mice using chamber graft assay when combined with epithelial stem cells. The method of isolating functional DP cells we established here lays a solid foundation for developing DP cell-based therapy. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Lipeng Gao
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Eve Qian Chen
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Hong-Bing Zhong
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Jing Xie
- Department of Dermatology, the Third Affiliated Hospital of Shanghai University (Wenzhou People's Hospital), Wenzhou, China
| | - Hong-Zhi Song
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Xu-Bo Zhao
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Lin-Ran Lin
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.,Department of Dermatology, Jing'an District Central Hospital, Shanghai, China
| | - Qingmei Liu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.,Department of Dermatology, Jing'an District Central Hospital, Shanghai, China
| | - Shihua Wang
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Wen-Yu Wu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.,Department of Dermatology, Jing'an District Central Hospital, Shanghai, China
| | - Robert Chunhua Zhao
- School of Life Sciences, Shanghai University, Shanghai, China.,Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xin-Hua Liao
- School of Life Sciences, Shanghai University, Shanghai, China
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Targeting GPCRs and Their Signaling as a Therapeutic Option in Melanoma. Cancers (Basel) 2022; 14:cancers14030706. [PMID: 35158973 PMCID: PMC8833576 DOI: 10.3390/cancers14030706] [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: 01/06/2022] [Revised: 01/27/2022] [Accepted: 01/27/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary Sixteen G-protein-coupled receptors (GPCRs) have been involved in melanogenesis or melanomagenesis. Here, we review these GPCRs, their associated signaling, and therapies. Abstract G-protein-coupled receptors (GPCRs) serve prominent roles in melanocyte lineage physiology, with an impact at all stages of development, as well as on mature melanocyte functions. GPCR ligands are present in the skin and regulate melanocyte homeostasis, including pigmentation. The role of GPCRs in the regulation of pigmentation and, consequently, protection against external aggression, such as ultraviolet radiation, has long been established. However, evidence of new functions of GPCRs directly in melanomagenesis has been highlighted in recent years. GPCRs are coupled, through their intracellular domains, to heterotrimeric G-proteins, which induce cellular signaling through various pathways. Such signaling modulates numerous essential cellular processes that occur during melanomagenesis, including proliferation and migration. GPCR-associated signaling in melanoma can be activated by the binding of paracrine factors to their receptors or directly by activating mutations. In this review, we present melanoma-associated alterations of GPCRs and their downstream signaling and discuss the various preclinical models used to evaluate new therapeutic approaches against GPCR activity in melanoma. Recent striking advances in our understanding of the structure, function, and regulation of GPCRs will undoubtedly broaden melanoma treatment options in the future.
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Boesmans W, Nash A, Tasnády KR, Yang W, Stamp LA, Hao MM. Development, Diversity, and Neurogenic Capacity of Enteric Glia. Front Cell Dev Biol 2022; 9:775102. [PMID: 35111752 PMCID: PMC8801887 DOI: 10.3389/fcell.2021.775102] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 12/09/2021] [Indexed: 12/15/2022] Open
Abstract
Enteric glia are a fascinating population of cells. Initially identified in the gut wall as the "support" cells of the enteric nervous system, studies over the past 20 years have unveiled a vast array of functions carried out by enteric glia. They mediate enteric nervous system signalling and play a vital role in the local regulation of gut functions. Enteric glial cells interact with other gastrointestinal cell types such as those of the epithelium and immune system to preserve homeostasis, and are perceptive to luminal content. Their functional versatility and phenotypic heterogeneity are mirrored by an extensive level of plasticity, illustrated by their reactivity in conditions associated with enteric nervous system dysfunction and disease. As one of the hallmarks of their plasticity and extending their operative relationship with enteric neurons, enteric glia also display neurogenic potential. In this review, we focus on the development of enteric glial cells, and the mechanisms behind their heterogeneity in the adult gut. In addition, we discuss what is currently known about the role of enteric glia as neural precursors in the enteric nervous system.
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Affiliation(s)
- Werend Boesmans
- Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Amelia Nash
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
| | - Kinga R. Tasnády
- Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Wendy Yang
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taiwan, Taiwan
| | - Lincon A. Stamp
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
| | - Marlene M. Hao
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
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Cerrizuela S, Vega-Lopez GA, Méndez-Maldonado K, Velasco I, Aybar MJ. The crucial role of model systems in understanding the complexity of cell signaling in human neurocristopathies. WIREs Mech Dis 2022; 14:e1537. [PMID: 35023327 DOI: 10.1002/wsbm.1537] [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: 03/30/2021] [Revised: 08/26/2021] [Accepted: 08/30/2021] [Indexed: 11/07/2022]
Abstract
Animal models are useful to study the molecular, cellular, and morphogenetic mechanisms underlying normal and pathological development. Cell-based study models have emerged as an alternative approach to study many aspects of human embryonic development and disease. The neural crest (NC) is a transient, multipotent, and migratory embryonic cell population that generates a diverse group of cell types that arises during vertebrate development. The abnormal formation or development of the NC results in neurocristopathies (NCPs), which are characterized by a broad spectrum of functional and morphological alterations. The impaired molecular mechanisms that give rise to these multiphenotypic diseases are not entirely clear yet. This fact, added to the high incidence of these disorders in the newborn population, has led to the development of systematic approaches for their understanding. In this article, we have systematically reviewed the ways in which experimentation with different animal and cell model systems has improved our knowledge of NCPs, and how these advances might contribute to the development of better diagnostic and therapeutic tools for the treatment of these pathologies. This article is categorized under: Congenital Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Stem Cells and Development Congenital Diseases > Molecular and Cellular Physiology Neurological Diseases > Genetics/Genomics/Epigenetics.
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Affiliation(s)
- Santiago Cerrizuela
- Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Instituto Superior de Investigaciones Biológicas (INSIBIO, CONICET-UNT), Tucumán, Argentina
| | - Guillermo A Vega-Lopez
- Instituto Superior de Investigaciones Biológicas (INSIBIO, CONICET-UNT), Tucumán, Argentina.,Instituto de Biología "Dr. Francisco D. Barbieri", Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Tucumán, Argentina
| | - Karla Méndez-Maldonado
- Instituto de Fisiología Celular - Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.,Departamento de Fisiología y Farmacología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Iván Velasco
- Instituto de Fisiología Celular - Neurociencias, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.,Laboratorio de Reprogramación Celular del Instituto de Fisiología Celular, UNAM en el Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suárez", Ciudad de México, Mexico
| | - Manuel J Aybar
- Instituto Superior de Investigaciones Biológicas (INSIBIO, CONICET-UNT), Tucumán, Argentina.,Instituto de Biología "Dr. Francisco D. Barbieri", Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Tucumán, Argentina
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34
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Lan C, Liu Y, Wu X, Wang B, Xin S, He Q, Zhong W, Liu Z. Susceptibility of ECE1 polymorphisms to Hirschsprung's disease in southern Chinese children. Front Pediatr 2022; 10:1056938. [PMID: 36619519 PMCID: PMC9813666 DOI: 10.3389/fped.2022.1056938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Hirschsprung's disease (HSCR) is currently considered to be a congenital gastrointestinal malformation caused mainly by genetic factors. Endothelin Converting Enzyme-1 (ECE1) has been reported to be associated with HSCR. However, the relationship between ECE1 single nucleotide polymorphism (SNP) rs169884 and HSCR in the southern Chinese population remains unknown. METHODS 1,470 HSCR patients and 1,473 controls from a southern Chinese population were recruited. The intronic SNP rs169884 in ECE1 was genotyped in all samples. We tested the association between rs169884 and HSCR under various genetic models. We also evaluated the effect of rs169884 on HSCR subtypes, including short-segment HSCR (S-HSCR), long-segment HSCR (L-HSCR) and total colonic aganglionosis (TCA). External epigenetic data were integrated to investigate the potential biological function of rs169884. RESULTS Chromatin states data from derived neuron cells or fetal colon tissue revealed that rs169884 might control ECE1 expression through regulating its enhancer function. We did not find a significant association between rs169884 and HSCR. For HSCR subtypes, although no significant associations were detected between rs169884 and S-HSCR (OR = 1.00, 95% CI: 0.89∼1.12, Padj = 0.77) or TCA (OR = 1.00, 95% CI: 0.72∼1.38, Padj = 0.94), we found that rs169884 could increase the risk of L-HSCR (OR = 1.23, 95% CI 1.02∼1.45, Padj = 0.024). CONCLUSION These results suggested that rs169884 might play a regulatory role for ECE1 expression and increase susceptibility of L-HSCR in southern Chinese children.
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Affiliation(s)
- Chaoting Lan
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yanqing Liu
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xiao Wu
- Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, China
| | - Bingtong Wang
- Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, China
| | | | - Qiuming He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Wei Zhong
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zipeng Liu
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
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35
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Torres Crigna A, Link B, Samec M, Giordano FA, Kubatka P, Golubnitschaja O. Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine. EPMA J 2021; 12:265-305. [PMID: 34367381 PMCID: PMC8334338 DOI: 10.1007/s13167-021-00248-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023]
Abstract
Endothelin-1 (ET-1) is involved in the regulation of a myriad of processes highly relevant for physical and mental well-being; female and male health; in the modulation of senses, pain, stress reactions and drug sensitivity as well as healing processes, amongst others. Shifted ET-1 homeostasis may influence and predict the development and progression of suboptimal health conditions, metabolic impairments with cascading complications, ageing and related pathologies, cardiovascular diseases, neurodegenerative pathologies, aggressive malignancies, modulating, therefore, individual outcomes of both non-communicable and infectious diseases such as COVID-19. This article provides an in-depth analysis of the involvement of ET-1 and related regulatory pathways in physiological and pathophysiological processes and estimates its capacity as a predictor of ageing and related pathologies,a sensor of lifestyle quality and progression of suboptimal health conditions to diseases for their targeted preventionand as a potent target for cost-effective treatments tailored to the person.
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Affiliation(s)
- Adriana Torres Crigna
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Barbara Link
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Marek Samec
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Frank A. Giordano
- Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Olga Golubnitschaja
- Predictive, Preventive and Personalised (3P) Medicine, Department of Radiation Oncology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
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36
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Chow LS, Bosnakovski D, Mashek DG, Kyba M, Perlingeiro RCR, Magli A. Chromatin accessibility profiling identifies evolutionary conserved loci in activated human satellite cells. Stem Cell Res 2021; 55:102496. [PMID: 34411972 PMCID: PMC8917817 DOI: 10.1016/j.scr.2021.102496] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/19/2021] [Accepted: 08/04/2021] [Indexed: 12/04/2022] Open
Abstract
Satellite cells represent the main myogenic population accounting for skeletal muscle homeostasis and regeneration. While our knowledge of the signaling pathways controlling satellite cell regenerative capability is increasing, the underlying epigenetic mechanisms are still not clear, especially in the case of human satellite cells. Here, by performing chromatin accessibility profiling (ATAC-seq) in samples isolated from human and murine muscles, we investigated the changes in the epigenetic landscape occurring during the transition from activated satellite cells to myoblasts. Our analysis identifies a compendium of putative regulatory elements defining human activated satellite cells and myoblasts, respectively. A subset of these differentially accessible loci is shared by both murine and human satellite cells, includes elements associated with known self-renewal regulators, and is enriched for motifs bound by transcription factors participating in satellite cell regulation. Integration of transcriptional and epigenetic data reveals that known regulators of metabolic gene expression, such as PPARGC1A, represent potential PAX7 targets. Through characterization of genomic networks and the underlying effectors, our data represent an important starting point for decoding and manipulating the molecular mechanisms underlying human satellite cell muscle regenerative potential.
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Affiliation(s)
- Lisa S Chow
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Darko Bosnakovski
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; University Goce Delcev - Shtip, Faculty of Medical Sciences, Shtip, Macedonia
| | - Douglas G Mashek
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Minnesota, Minneapolis, MN, USA; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Michael Kyba
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
| | - Rita C R Perlingeiro
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA; Division of Cardiology, Department of Medicine, University of Minnesota, Minneapolis, MN USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
| | - Alessandro Magli
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA; Division of Cardiology, Department of Medicine, University of Minnesota, Minneapolis, MN USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
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Nerve-associated Schwann cell precursors contribute extracutaneous melanocytes to the heart, inner ear, supraorbital locations and brain meninges. Cell Mol Life Sci 2021; 78:6033-6049. [PMID: 34274976 PMCID: PMC8316242 DOI: 10.1007/s00018-021-03885-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/07/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023]
Abstract
Melanocytes are pigmented cells residing mostly in the skin and hair follicles of vertebrates, where they contribute to colouration and protection against UV-B radiation. However, the spectrum of their functions reaches far beyond that. For instance, these pigment-producing cells are found inside the inner ear, where they contribute to the hearing function, and in the heart, where they are involved in the electrical conductivity and support the stiffness of cardiac valves. The embryonic origin of such extracutaneous melanocytes is not clear. We took advantage of lineage-tracing experiments combined with 3D visualizations and gene knockout strategies to address this long-standing question. We revealed that Schwann cell precursors are recruited from the local innervation during embryonic development and give rise to extracutaneous melanocytes in the heart, brain meninges, inner ear, and other locations. In embryos with a knockout of the EdnrB receptor, a condition imitating Waardenburg syndrome, we observed only nerve-associated melanoblasts, which failed to detach from the nerves and to enter the inner ear. Finally, we looked into the evolutionary aspects of extracutaneous melanocytes and found that pigment cells are associated mainly with nerves and blood vessels in amphibians and fish. This new knowledge of the nerve-dependent origin of extracutaneous pigment cells might be directly relevant to the formation of extracutaneous melanoma in humans.
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38
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Bovo S, Schiavo G, Kazemi H, Moscatelli G, Ribani A, Ballan M, Bonacini M, Prandi M, Dall'Olio S, Fontanesi L. Exploiting within-breed variability in the autochthonous Reggiana breed identified several candidate genes affecting pigmentation-related traits, stature and udder defects in cattle. Anim Genet 2021; 52:579-597. [PMID: 34182594 PMCID: PMC8519023 DOI: 10.1111/age.13109] [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] [Accepted: 06/11/2021] [Indexed: 01/13/2023]
Abstract
Autochthonous cattle breeds constitute important reservoirs of genetic diversity. Reggiana is an Italian local cattle breed reared in the north of Italy for the production of a mono‐breed Parmigiano–Reggiano cheese. Reggiana cattle usually have a classical solid red coat colour and pale muzzle. As part of the strategies designed for the sustainable conservation of this genetic resource, we investigated at the genome‐wise level the within‐breed detected variability of three pigmentation‐related traits (intensity of red coat colour, based on three classes – light/diluted, normal and dark; spotted patterns/piebaldism that sometime emerge in the breed; muzzle colour – pink/pale, grey and black), stature, presence/absence and number of supernumerary teats and teat length. A total of 1776 Reggiana cattle (about two‐thirds of the extant breed population) were genotyped with the GeneSeek GGP Bovine 150k SNP array and single‐marker and haplotype‐based GWASs were carried out. The results indicated that two main groups of genetic factors affect the intensity of red coat colour: darkening genes (including EDN3 and a few other genes) and diluting genes (including PMEL and a few other genes). Muzzle colour was mainly determined by MC1R gene markers. Piebaldism was mainly associated with KIT gene markers. Stature was associated with BTA6 markers upstream of the NCAPG–LCORL genes. Teat defects were associated with TBX3/TBX5, MCC and LGR5 genes. Overall, the identified genomic regions not only can be directly used in selection plans in the Reggiana breed, but also contribute to clarifying the genetic mechanisms involved in determining exterior traits in cattle.
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Affiliation(s)
- S Bovo
- Division of Animal Sciences, Department of Agricultural and Food Science, University of Bologna, Viale Giuseppe Fanin 46, Bologna, 40127, Italy
| | - G Schiavo
- Division of Animal Sciences, Department of Agricultural and Food Science, University of Bologna, Viale Giuseppe Fanin 46, Bologna, 40127, Italy
| | - H Kazemi
- Division of Animal Sciences, Department of Agricultural and Food Science, University of Bologna, Viale Giuseppe Fanin 46, Bologna, 40127, Italy
| | - G Moscatelli
- Division of Animal Sciences, Department of Agricultural and Food Science, University of Bologna, Viale Giuseppe Fanin 46, Bologna, 40127, Italy
| | - A Ribani
- Division of Animal Sciences, Department of Agricultural and Food Science, University of Bologna, Viale Giuseppe Fanin 46, Bologna, 40127, Italy
| | - M Ballan
- Division of Animal Sciences, Department of Agricultural and Food Science, University of Bologna, Viale Giuseppe Fanin 46, Bologna, 40127, Italy
| | - M Bonacini
- Associazione Nazionale Allevatori Bovini di Razza Reggiana (ANABORARE), Via Masaccio 11, Reggio Emilia, 42124, Italy
| | - M Prandi
- Associazione Nazionale Allevatori Bovini di Razza Reggiana (ANABORARE), Via Masaccio 11, Reggio Emilia, 42124, Italy
| | - S Dall'Olio
- Division of Animal Sciences, Department of Agricultural and Food Science, University of Bologna, Viale Giuseppe Fanin 46, Bologna, 40127, Italy
| | - L Fontanesi
- Division of Animal Sciences, Department of Agricultural and Food Science, University of Bologna, Viale Giuseppe Fanin 46, Bologna, 40127, Italy
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Chen KC, Song ZM, Croaker GD. Brain size reductions associated with endothelin B receptor mutation, a cause of Hirschsprung's disease. BMC Neurosci 2021; 22:42. [PMID: 34147087 PMCID: PMC8214790 DOI: 10.1186/s12868-021-00646-z] [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: 06/20/2020] [Accepted: 06/08/2021] [Indexed: 01/03/2023] Open
Abstract
Background ETB has been reported to regulate neurogenesis and vasoregulation in foetal development. Its dysfunction was known to cause HSCR, an aganglionic colonic disorder with syndromic forms reported to associate with both small heads and developmental delay. We therefore asked, "is CNS maldevelopment a more general feature of ETB mutation?" To investigate, we reviewed the micro-CT scans of an ETB−/− model animal, sl/sl rat, and quantitatively evaluated the structural changes of its brain constituents. Methods Eleven neonatal rats generated from ETB+/− cross breeding were sacrificed. Micro-CT scans were completed following 1.5% iodine-staining protocols. All scans were reviewed for morphological changes. Selected organs were segmented semi-automatically post-NLM filtering: TBr, T-CC, T-CP, OB, Med, Cer, Pit, and S&I Col. Volumetric measurements were made using Drishti rendering software. Rat genotyping was completed following analysis. Statistical comparisons on organ volume, organ growth rate, and organ volume/bodyweight ratios were made between sl/sl and the control groups based on autosomal recessive inheritance. One-way ANOVA was also performed to evaluate potential dose-dependent effect. Results sl/sl rat has 16.32% lower body weight with 3.53% lower growth rate than the control group. Gross intracranial morphology was preserved in sl/sl rats. However, significant volumetric reduction of 20.33% was detected in TBr; similar reductions were extended to the measurements of T-CC, T-CP, OB, Med, and Pit. Consistently, lower brain and selected constituent growth rates were detected in sl/sl rat, ranging from 6.21% to 11.51% reduction. Lower organ volume/bodyweight ratio was detected in sl/sl rats, reflecting disproportional neural changes with respect to body size. No consistent linear relationships exist between ETB copies and intracranial organ size or growth rates. Conclusion Although ETB−/− mutant has a normal CNS morphology, significant size reductions in brain and constituents were detected. These structural changes likely arise from a combination of factors secondary to dysfunctional ET-1/ET-3/ETB signalling, including global growth impairment from HSCR-induced malnutrition and dysregulations in the neurogenesis, angiogenesis, and cerebral vascular control. These changes have important clinical implications, such as autonomic dysfunction or intellectual delay. Although further human study is warranted, our study suggested comprehensive managements are required for HSCR patients, at least in ETB−/− subtype. Supplementary Information The online version contains supplementary material available at 10.1186/s12868-021-00646-z.
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Affiliation(s)
- Ko-Chin Chen
- Medical School, Australian National University, Canberra, ACT, 2601, Australia.
| | - Zan-Min Song
- Medical School, Australian National University, Canberra, ACT, 2601, Australia
| | - Geoffrey D Croaker
- Medical School, Australian National University, Canberra, ACT, 2601, Australia.,The Canberra Hospital, Yamba Drive, Garran, ACT, 2605, Australia
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40
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Abstract
Congenital hearing loss is the most common birth defect, estimated to affect 2-3 in every 1000 births. Currently there is no cure for hearing loss. Treatment options are limited to hearing aids for mild and moderate cases, and cochlear implants for severe and profound hearing loss. Here we provide a literature overview of the environmental and genetic causes of congenital hearing loss, common animal models and methods used for hearing research, as well as recent advances towards developing therapies to treat congenital deafness. © 2021 The Authors.
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Affiliation(s)
- Justine M Renauld
- Department of Otolaryngology, Head & Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Martin L Basch
- Department of Otolaryngology, Head & Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio.,Department of Genetics and Genome Sciences, Case Western Reserve School of Medicine, Cleveland, Ohio.,Department of Biology, Case Western Reserve University, Cleveland, Ohio.,Department of Otolaryngology, Head & Neck Surgery, University Hospitals, Cleveland, Ohio
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41
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Miwa T, Ito N, Ohta K. Tsukushi is essential for the formation of the posterior semicircular canal that detects gait performance. J Cell Commun Signal 2021; 15:581-594. [PMID: 34061311 DOI: 10.1007/s12079-021-00627-1] [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: 01/27/2021] [Accepted: 05/25/2021] [Indexed: 11/27/2022] Open
Abstract
Tsukushi is a small, leucine-rich repeat proteoglycan that interacts with and regulates essential cellular signaling cascades in the chick retina and murine subventricular zone, hippocampus, dermal hair follicles, and the cochlea. However, its function in the vestibules of the inner ear remains unknown. Here, we investigated the function of Tsukushi in the vestibules and found that Tsukushi deficiency in mice resulted in defects in posterior semicircular canal formation in the vestibules, but did not lead to vestibular hair cell loss. Furthermore, Tsukushi accumulated in the non-prosensory and prosensory regions during the embryonic and postnatal developmental stages. The downregulation of Tsukushi altered the expression of key genes driving vestibule differentiation in the non-prosensory regions. Our results indicate that Tsukushi interacts with Wnt2b, bone morphogenetic protein 4, fibroblast growth factor 10, and netrin 1, thereby controlling semicircular canal formation. Therefore, Tsukushi may be an essential component of the molecular pathways regulating vestibular development.
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Affiliation(s)
- Toru Miwa
- Department of Otolaryngology-Head and Neck Surgery, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Ougimaci, Kita-ku, Osaka, Japan.
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kumamoto University, Honjo, Kumamoto, Japan.
| | - Naofumi Ito
- Department of Developmental Neurobiology, Graduate School of Life Sciences, Kumamoto University, Honjo, Kumamoto, Japan
- K.K. Sciex Japan, Shinagawa, Tokyo, Japan
| | - Kunimasa Ohta
- Department of Stem Cell Biology, Faculty of Arts and Science, Kyushu University, Motooka, Nishi-ku, Fukuoka, Japan
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Araya-Donoso R, San Juan E, Tamburrino Í, Lamborot M, Veloso C, Véliz D. Integrating genetics, physiology and morphology to study desert adaptation in a lizard species. J Anim Ecol 2021; 91:1148-1162. [PMID: 34048024 DOI: 10.1111/1365-2656.13546] [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: 04/28/2020] [Accepted: 05/24/2021] [Indexed: 11/28/2022]
Abstract
Integration of multiple approaches is key to understand the evolutionary processes of local adaptation and speciation. Reptiles have successfully colonized desert environments, that is, extreme and arid conditions that constitute a strong selective pressure on organisms. Here, we studied genomic, physiological and morphological variations of the lizard Liolaemus fuscus to detect adaptations to the Atacama Desert. By comparing populations of L. fuscus inhabiting the Atacama Desert with populations from the Mediterranean forests from central Chile, we aimed at characterizing features related to desert adaptation. We combined ddRAD sequencing with physiological (evaporative water loss, metabolic rate and selected temperature) and morphological (linear and geometric morphometrics) measurements. We integrated the genomic and phenotypic data using redundancy analyses. Results showed strong genetic divergence, along with a high number of fixed loci between desert and forest populations. Analyses detected 110 fixed and 30 outlier loci located within genes, from which 43 were in coding regions, and 12 presented non-synonymous mutations. The candidate genes were associated with cellular membrane and development. Desert lizards presented lower evaporative water loss than those from the forest. Morphological data showed that desert lizards had smaller body size, different allometry, larger eyeballs and more dorsoventrally compressed heads. Our results suggest incipient speciation between desert and forest populations. The adaptive signal must be cautiously interpreted since genetic drift could also contribute to the divergence pattern. Nonetheless, we propose water and resource availability, and changes in habitat structure, as the most relevant challenges for desert reptiles. This study provides insights of the mechanisms that allow speciation as well as desert adaptation in reptiles at multiple levels, and highlights the benefit of integrating independent evidence.
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Affiliation(s)
- Raúl Araya-Donoso
- Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.,Núcleo Milenio de Ecología y Manejo Sustentable de Islas Oceánicas (ESMOI), Departamento de Biología Marina, Universidad Católica del Norte, Coquimbo, Chile.,School of Life Sciences, Arizona State University, Tempe, AZ, USA
| | - Esteban San Juan
- Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Ítalo Tamburrino
- Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Madeleine Lamborot
- Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Claudio Veloso
- Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - David Véliz
- Departamento de Ciencias Ecológicas, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.,Núcleo Milenio de Ecología y Manejo Sustentable de Islas Oceánicas (ESMOI), Departamento de Biología Marina, Universidad Católica del Norte, Coquimbo, Chile
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43
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Upadhyay PR, Ho T, Abdel-Malek ZA. Participation of keratinocyte- and fibroblast-derived factors in melanocyte homeostasis, the response to UV, and pigmentary disorders. Pigment Cell Melanoma Res 2021; 34:762-776. [PMID: 33973367 DOI: 10.1111/pcmr.12985] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/19/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022]
Abstract
Human epidermal melanocytes play a central role in sensing the environment and protecting the skin from the drastic effects of solar ultraviolet radiation and other environmental toxins or inflammatory agents. Melanocytes survive in the epidermis for decades, which subjects them to chronic environmental insults. Melanocytes have a poor self-renewal capacity; therefore, it is critical to ensure their survival with genomic stability. The function and survival of melanocytes is regulated by an elaborate network of paracrine factors synthesized mainly by epidermal keratinocytes and dermal fibroblasts. A symbiotic relationship exists between epidermal melanocytes and keratinocytes on the one hand, and between melanocytes and dermal fibroblasts on the other hand. Melanocytes protect epidermal keratinocytes and dermal fibroblasts from the damaging effects of solar radiation, and the latter cells synthesize biochemical mediators that maintain the homeostasis, and regulate the stress response of melanocytes. Disruption of the paracrine network results in pigmentary disorders, due to abnormal regulation of melanin synthesis, and compromise of melanocyte survival or genomic stability. This review provides an update of the current knowledge of keratinocyte- and fibroblast-derived paracrine factors and their contribution to melanocyte physiology, and how their abnormal production is involved in the pathogenesis of common pigmentary disorders.
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Affiliation(s)
- Parth R Upadhyay
- Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.,Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA
| | - Tina Ho
- Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Zalfa A Abdel-Malek
- Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Koyama Y. Endothelin ET B Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders. Int J Mol Sci 2021; 22:ijms22094333. [PMID: 33919338 PMCID: PMC8122402 DOI: 10.3390/ijms22094333] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 12/11/2022] Open
Abstract
In brain disorders, reactive astrocytes, which are characterized by hypertrophy of the cell body and proliferative properties, are commonly observed. As reactive astrocytes are involved in the pathogenesis of several brain disorders, the control of astrocytic function has been proposed as a therapeutic strategy, and target molecules to effectively control astrocytic functions have been investigated. The production of brain endothelin-1 (ET-1), which increases in brain disorders, is involved in the pathophysiological response of the nervous system. Endothelin B (ETB) receptors are highly expressed in reactive astrocytes and are upregulated by brain injury. Activation of astrocyte ETB receptors promotes the induction of reactive astrocytes. In addition, the production of various astrocyte-derived factors, including neurotrophic factors and vascular permeability regulators, is regulated by ETB receptors. In animal models of Alzheimer’s disease, brain ischemia, neuropathic pain, and traumatic brain injury, ETB-receptor-mediated regulation of astrocytic activation has been reported to improve brain disorders. Therefore, the astrocytic ETB receptor is expected to be a promising drug target to improve several brain disorders. This article reviews the roles of ETB receptors in astrocytic activation and discusses its possible applications in the treatment of brain disorders.
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Affiliation(s)
- Yutaka Koyama
- Laboratory of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyama-Kita Higashinada, Kobe 668-8558, Japan
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45
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Gershon MD. Hirschsprung disease and more: dysregulation of ERBB2 and ERBB3. J Clin Invest 2021; 131:146389. [PMID: 33720042 DOI: 10.1172/jci146389] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The enteric nervous system mediates reflexes independently of the brain and spinal cord and transmits signals bidirectionally between the gut and the brain. Hirschsprung disease and chronic intestinal pseudo-obstruction (CIPO) and pediatric CIPO are examples of congenital defects that impair gastrointestinal motility. In this issue of the JCI, Thuy-Linh Le et al. analyzed eight patients with defects in tissue that arose from the neural crest. The patients carried homozygous or heterozygous variants in ERBB3 or ERBB2, which encode transmembrane epidermal growth factor receptors that bind neuroregulin 1 (NRG1). Notably, the genetic variants resulted in loss of function with decreased expression or aberrant phosphorylation of the ERBB3/ERBB2 receptors. Experiments using mice revealed that Erbb3 and Erbb2 were expressed in enteric neuronal progenitor cells. This study is an outstanding example of descriptive observation that begs for mechanistic exploration to reveal precisely how the NRG1/ERBB3/ERBB2 pathway influences ENS development.
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46
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Ullate-Agote A, Tzika AC. Characterization of the Leucistic Texas Rat Snake Pantherophis obsoletus. Front Ecol Evol 2021. [DOI: 10.3389/fevo.2021.583136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Albinism and leucism are phenotypes resulting from impaired melanin pigmentation in the skin and skin appendages. However, melanin pigmentation of eyes remains unaffected in leucism. Here, using transmission electron microscopy, we show that the leucistic morph of the Texas rat snake (Pantherophis obsoletus lindheimeri) lacks both melanophores and xanthophores in its skin and exhibits a uniform ivory white color generated by iridophores and collagen fibers. In addition, we sequenced the full genome of a leucistic individual and obtained a highly-contiguous near-chromosome quality assembly of 1.69 Gb with an N50 of 14.5 Mb and an L50 of 29 sequences. Using a candidate-gene approach, we then identify in the leucistic genome a single-nucleotide deletion that generates a frameshift and a premature termination codon in the melanocyte inducing transcription factor (MITF) gene. This mutation shortens the translated protein from 574 to 286 amino acids, removing the helix-loop-helix DNA-binding domain that is highly conserved among vertebrates. Genotyping leucistic animals of independent lineages showed that not all leucistic individuals carry this single-nucleotide deletion. Subsequent gene expression analyses reveal that all leucistic individuals that we analyzed exhibit a significantly decreased expression of MITF. We thus suggest that mutations affecting the regulation and, in some cases, the coding sequence of MITF, the former probably predating the latter, could be associated with the leucistic phenotype in Texas rat snakes. MITF is involved in the development and survival of melanophores in vertebrates. In zebrafish, a classical model species for pigmentation that undergoes metamorphosis, larvae and adults of homozygous mitfa mutants lack melanophores, show an excess of iridophores and exhibit reduced yellow pigmentation. On the contrary, in the leucistic Texas rat snake, a non-metamorphic species, only iridophores persist. Our results suggest that fate determination of neural-crest derived melanophores and xanthophores, but not of iridophores, could require the expression of MITF during snake embryonic development.
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Ohara Y, Fujimura L, Sakamoto A, Teratake Y, Hiraoka S, Koseki H, Saito T, Terui K, Mitsunaga T, Nakata M, Yoshida H, Hatano M. Genetic background-dependent abnormalities of the enteric nervous system and intestinal function in Kif26a-deficient mice. Sci Rep 2021; 11:3191. [PMID: 33542431 PMCID: PMC7862435 DOI: 10.1038/s41598-021-82785-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 01/26/2021] [Indexed: 12/21/2022] Open
Abstract
The Kif26a protein-coding gene has been identified as a negative regulator of the GDNF-Ret signaling pathway in enteric neurons. The aim of this study was to investigate the influence of genetic background on the phenotype of Kif26a-deficient (KO, -/-) mice. KO mice with both C57BL/6 and BALB/c genetic backgrounds were established. Survival rates and megacolon development were compared between these two strains of KO mice. Functional bowel assessments and enteric neuron histopathology were performed in the deficient mice. KO mice with the BALB/c genetic background survived more than 400 days without evidence of megacolon, while all C57BL/6 KO mice developed megacolon and died within 30 days. Local enteric neuron hyperplasia in the colon and functional bowel abnormalities were observed in BALB/c KO mice. These results indicated that megacolon and enteric neuron hyperplasia in KO mice are influenced by the genetic background. BALB/c KO mice may represent a viable model for functional gastrointestinal diseases such as chronic constipation, facilitating studies on the underlying mechanisms and providing a foundation for the development of treatments.
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Affiliation(s)
- Yukiko Ohara
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Lisa Fujimura
- Biomedical Research Center, Chiba University, Chiba, Japan
| | - Akemi Sakamoto
- Biomedical Research Center, Chiba University, Chiba, Japan.,Department of Biomedical Science, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuoku, Chiba City, Chiba, 260-8670, Japan
| | | | - Shuichi Hiraoka
- Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (RIKEN-IMS), Yokohama, Japan
| | - Haruhiko Koseki
- Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences (RIKEN-IMS), Yokohama, Japan.,Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takeshi Saito
- Department of Pediatric Surgery, Chiba Children's Hospital, Chiba, Japan
| | - Keita Terui
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuya Mitsunaga
- Department of Pediatric Surgery, Chiba Children's Hospital, Chiba, Japan
| | - Mitsuyuki Nakata
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hideo Yoshida
- Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masahiko Hatano
- Biomedical Research Center, Chiba University, Chiba, Japan. .,Department of Biomedical Science, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuoku, Chiba City, Chiba, 260-8670, Japan.
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Renauld JM, Davis W, Cai T, Cabrera C, Basch ML. Transcriptomic analysis and ednrb expression in cochlear intermediate cells reveal developmental differences between inner ear and skin melanocytes. Pigment Cell Melanoma Res 2021; 34:585-597. [PMID: 33484097 PMCID: PMC8186279 DOI: 10.1111/pcmr.12961] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 12/29/2020] [Accepted: 01/16/2021] [Indexed: 12/22/2022]
Abstract
In the inner ear, the neural crest gives rise to the glia of the VIII ganglion and two types of melanocytic cells: The pigmented cells of the vestibular system and intermediate cells of the stria vascularis. We analyzed the transcriptome of neonatal intermediate cells in an effort to better understand the development of the stria vascularis. We found that the expression of endothelin receptor B, which is essential for melanocyte development, persists in intermediate cells long after birth. In contrast, skin melanocytes rapidly downregulate the expression of EdnrB. Our findings suggest that endothelins might have co‐opted new functions in the inner ear during evolution of the auditory organ.
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Affiliation(s)
- Justine M Renauld
- Department of Otolaryngology, Head & Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - William Davis
- Department of Otolaryngology, Head & Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Tiantian Cai
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA
| | - Claudia Cabrera
- Department of Otolaryngology, Head & Neck Surgery, University Hospitals, Cleveland, OH, USA
| | - Martin L Basch
- Department of Otolaryngology, Head & Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA.,Department of Otolaryngology, Head & Neck Surgery, University Hospitals, Cleveland, OH, USA.,Department of Genetics and Genome Sciences, Case Western Reserve School of Medicine, Cleveland, OH, USA.,Department of Biology, Case Western Reserve School of Medicine, Cleveland, OH, USA
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49
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Gulati A, Agrawal N, Vibha D, Misra UK, Paul B, Jain D, Pandian J, Borgohain R. Safety and Efficacy of Sovateltide (IRL-1620) in a Multicenter Randomized Controlled Clinical Trial in Patients with Acute Cerebral Ischemic Stroke. CNS Drugs 2021; 35:85-104. [PMID: 33428177 PMCID: PMC7872992 DOI: 10.1007/s40263-020-00783-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/05/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, has been previously shown to increase cerebral blood flow, have anti-apoptotic activity and produce neurovascular remodeling when administered intravenously following acute cerebral ischemic stroke in rats. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509). OBJECTIVE Our objective was to determine the safety, tolerability and efficacy of sovateltide as an addition to standard of care (SOC) in patients with acute cerebral ischemic stroke. METHODS A prospective, multicentric, randomized, double-blind, placebo-controlled study was conducted to compare the safety (primary objective) and efficacy (secondary objective) of sovateltide in patients with acute cerebral ischemic stroke. Adult males or females aged 18-70 years who had experienced a radiologically confirmed ischemic stroke within the last 24 h were included in the study. Patients with intracranial hemorrhage and those receiving endovascular therapy were excluded. Patients randomized to the sovateltide group received three doses of sovateltide (each dose 0.3 µg/kg) administered as an intravenous bolus over 1 min at an interval of 3 ± 1 h on day 1, day 3 and day 6 (total dose of 0.9 µg/kg/day). Patients randomized to the placebo group received an equal volume of saline. Every patient in both groups received SOC for stroke. Efficacy was evaluated using neurological outcomes based on National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) scores from day 1 through day 90. Quality of life was measured using the EuroQoL-5 Dimensions (EQ-5D) and Stroke-Specific Quality of Life (SSQoL) at 60 and 90 days of follow-up. RESULTS A total of 40 patients with acute cerebral ischemic stroke were enrolled in this study, of whom 36 completed the 90-day follow-up. Patients received saline (n = 18; 11 male and 7 female) or sovateltide (n = 18; 15 male and 3 female) within 24 h of onset of stroke. The number of patients receiving investigational drug within 20 h of onset of stroke was 14/18 in the saline group and 10/18 in the sovateltide group. The baseline characteristics and SOC in both cohorts was similar. Sovateltide was well-tolerated, and all patients received complete treatment with no incidence of drug-related adverse events. Hemodynamic, biochemical or hematological parameters were not affected by sovateltide. Sovateltide treatment resulted in improved mRS and BI scores on day 6 compared with day 1 (p < 0.0001), an effect not seen in the saline group. Sovateltide increased the frequency of favorable outcomes at 3 months. An improvement of ≥ 2 points on the mRS was observed in 60 and 40% of patients in the sovateltide and saline groups, respectively (p = 0.0519; odds ratio [OR] 5.25). An improvement on the BI of ≥ 40 points was seen in 64 and 36% of the sovateltide and saline groups, respectively (p = 0.0112; OR 12.44). An improvement of ≥6 points on the NIHSS was seen in 56% of patients in the sovateltide group versus 43% in the saline group (p = 0.2714; OR 2.275). The number of patients with complete recovery (defined as an NIHSS score of 0 and a BI of 100) was significantly greater (p < 0.05) in the sovateltide group than in the saline group. An assessment of complete recovery using an mRS score of 0 did not show a statistically significant difference between the treatment groups. Sovateltide treatment resulted in improved quality of life as measured by the EQ-5D and SSQoL on day 90. CONCLUSION Sovateltide was safe and well-tolerated and resulted in improved neurological outcomes in patients with acute cerebral ischemic stroke 90 days post-treatment. TRIAL REGISTRATION The study is registered at CTRI/2017/11/010654 and NCT04046484.
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Affiliation(s)
- Anil Gulati
- Pharmazz, Inc., 50 West 75th Street, Suite 105, Willowbrook, IL, 60527, USA.
- Midwestern University, Downers Grove, IL, USA.
| | | | - Deepti Vibha
- All India Inst of Medical Sciences, New Delhi, India
| | - U K Misra
- Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Jasim KA, Waheed IF, Topps M, Gesquiere AJ. Multifunctional system for combined chemodynamic–photodynamic therapy employing the endothelin axis based on conjugated polymer nanoparticles. Polym Chem 2021. [DOI: 10.1039/d1py00964h] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Most nanomedicines that attack tumors by Reactive Oxygen Species (ROS) based on lipid peroxidation mechanisms require external activation to work.
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Affiliation(s)
- Khalaf A. Jasim
- Department of Chemistry, College of Science, Tikrit University, Tikrit 34001, Iraq
| | - Ibrahim F. Waheed
- Department of Chemistry, College of Science, Tikrit University, Tikrit 34001, Iraq
| | - Martin Topps
- NanoScience Technology Center, University of Central Florida, Orlando, FL 32826, USA
- Department of Chemistry, University of Central Florida, Orlando, FL 32826, USA
| | - Andre J. Gesquiere
- NanoScience Technology Center, University of Central Florida, Orlando, FL 32826, USA
- Department of Chemistry, University of Central Florida, Orlando, FL 32826, USA
- Department of Materials Science and Engineering, University of Central Florida, Orlando, FL 32826, USA
- The College of Optics and Photonics (CREOL), University of Central Florida, Orlando, FL 32826, USA
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