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Bhasker A, Veleri S. Fundamental origins of neural tube defects with a basis in genetics and nutrition. Exp Brain Res 2025; 243:79. [PMID: 40025180 DOI: 10.1007/s00221-025-07016-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 01/30/2025] [Indexed: 03/04/2025]
Abstract
Neural tube defects (NTDs) are leading congenital malformations. Its global prevalence is one in 1000 pregnancies and it has high morbidity and mortality. It has multiple risk factors like genetic errors and environmental stressors like maternal malnutrition and in utero exposure to pollutants like chemicals. The genetic program determines neural tube development based on timely expression of many genes involved in developmental signaling pathways like BMP, PCP and SHH. BMP expression defines ectoderm. SOX represses BMP in ectoderm and convertes to the neuroectoderm. Subsequently, PCP molecules define the tissue patterning for convergent-extension, a critical step in neural tube genesis. Further, SHH sets spatial patterning of the neural tube. Nutrients are the essential major environmental input for embryogenesis. But it may also carry risk factors. Malnutrition, especially folate deficiency, during embryogenesis is a major cause for NTDs. Folate is integral in the One Carbon metabolic pathway. Its deficiency and error in the pathway are implicated in NTDs. Folate supplementation alone is insufficient to prevent NTDs. Thus, a comprehensive understanding of the various risk factors is necessary to strategize reduction of NTDs. We review the current knowledge of various risk factors, like genetic, metabolic, nutritional, and drugs causing NTDs and discuss the steps required to identify them in the early embryogenesis to avoid NTDs.
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Affiliation(s)
- Anjusha Bhasker
- Drug Safety Division, ICMR-National Institute of Nutrition, Department of Health Research, Ministry of Health & Family Welfare, Govt. of India, Hyderabad, 500007, India
| | - Shobi Veleri
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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2
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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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Lambert KA, Clements CM, Mukherjee N, Pacheco TR, Shellman SX, Henen MA, Vögeli B, Goldstein NB, Birlea S, Hintzsche J, Caryotakis G, Tan AC, Zhao R, Norris DA, Robinson WA, Wang Y, VanTreeck JG, Shellman YG. SASH1 S519N Variant Links Skin Hyperpigmentation and Premature Hair Graying to Dysfunction of Melanocyte Lineage. J Invest Dermatol 2025; 145:144-154.e3. [PMID: 38848986 PMCID: PMC11621233 DOI: 10.1016/j.jid.2024.04.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 04/08/2024] [Accepted: 04/09/2024] [Indexed: 06/09/2024]
Abstract
A better understanding of human melanocyte (MC) and MC stem cell biology is essential for treating MC-related diseases. This study employed an inherited pigmentation disorder carrying the SASH1S519N variant in a Hispanic family to investigate SASH1 function in the MC lineage and the underlying mechanism for this disorder. We used a multidisciplinary approach, including clinical examinations, human cell assays, yeast 2-hybrid screening, and biochemical techniques. Results linked early hair graying to the SASH1S519N variant, a previously unrecognized clinical phenotype in hyperpigmentation disorders. In vitro, we identified SASH1 as a regulator in MC stem cell maintenance and discovered that TNKS2 is crucial for SASH1's role. In addition, the S519N variant is located in one of multiple tankyrase-binding motifs and alters the binding kinetics and affinity of the interaction. In summary, this disorder links both gain and loss of pigmentation in the same individual, hinting to accelerated aging in human MC stem cells. The findings offer insights into the roles of SASH1 and TNKS2 in MC stem cell maintenance and the molecular mechanisms of pigmentation disorders. We propose that a comprehensive clinical evaluation of patients with MC-related disorders should include an assessment and history of hair pigmentation loss.
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Affiliation(s)
- Karoline A Lambert
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA
| | - Christopher M Clements
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA
| | - Nabanita Mukherjee
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA
| | - Theresa R Pacheco
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA
| | - Samantha X Shellman
- Department of Computer Science, University of Colorado Boulder, Boulder, Colorado, USA
| | - Morkos A Henen
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA
| | - Beat Vögeli
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA
| | - Nathaniel B Goldstein
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA
| | - Stanca Birlea
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA; Gates Institute, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | | | - Griffin Caryotakis
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA; Department of Biomedical Informatics, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
| | - Aik-Choon Tan
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA; Department of Biomedical Informatics, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
| | - Rui Zhao
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA
| | - David A Norris
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA
| | - William A Robinson
- Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA
| | - Yizhou Wang
- Department of Chemistry, College of Arts and Sciences, Emory University, Atlanta, Georgia, USA
| | - Jillian G VanTreeck
- College of Biological Sciences, University of Minnesota, Twin Cities, St. Paul, Minnesota, USA
| | - Yiqun G Shellman
- Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA; Gates Institute, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
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Mujica PC, Martinez V. A purebred South American breed showing high effective population size and independent breed ancestry: The Chilean Terrier. Anim Genet 2023; 54:772-785. [PMID: 37778752 DOI: 10.1111/age.13359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/31/2023] [Accepted: 09/09/2023] [Indexed: 10/03/2023]
Abstract
The Chilean Terrier is a known breed in Chile that has not been genetically assessed despite its distinctive color patterns, agility, and hardiness across the diversity of climates encountered within the Chilean landscape. The population structure and its relatedness with other breeds, as well as the actual origin of the breed, remain unknown. We estimated several population parameters using samples from individuals representing the distribution of the Chilean Terrier across the country. By utilizing the Illumina HD canine genotyping array, we computed the effective population size (Ne ), individual inbreeding, and relatedness to evaluate the genetic diversity of the breed. The results show that linkage disequilibrium was relatively low and decayed rapidly; in fact, Ne was very high when compared to other breeds, and similar to other American indigenous breeds (such as the Chihuahua with values of Ne near 500). These results are in line with the low estimates of genomic inbreeding and relatedness and the relatively large number of effective chromosome segments (Me = 2467) obtained using the properties of the genomic relationship matrix. Between population analysis (cross-population extended haplotype homozygosity, di ) with other breeds such as the Jack Russell Terrier, the Peruvian-Inca Orchid, and the Chihuahua suggested that candidate regions harboring FGF5, PAX3, and ASIP, probably explained some morphological traits, such as the distinctive color pattern characteristic of the breed. When considering Admixture estimates and phylogenetic analysis, together with other breeds of American and European origin, the Chilean Terrier does not have a recent European ancestry. Overall, the results suggest that the breed has evolved independently in Chile from other terrier breeds, from an unknown European terrier ancestor.
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Affiliation(s)
- Paola C Mujica
- FAVET-INBIOGEN Laboratory, Faculty of Veterinary Sciences, Universidad de Chile, Santiago, Chile
| | - Víctor Martinez
- FAVET-INBIOGEN Laboratory, Faculty of Veterinary Sciences, Universidad de Chile, Santiago, Chile
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Subhadarshini S, Sahoo S, Debnath S, Somarelli JA, Jolly MK. Dynamical modeling of proliferative-invasive plasticity and IFNγ signaling in melanoma reveals mechanisms of PD-L1 expression heterogeneity. J Immunother Cancer 2023; 11:e006766. [PMID: 37678920 PMCID: PMC10496669 DOI: 10.1136/jitc-2023-006766] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2023] [Indexed: 09/09/2023] Open
Abstract
BACKGROUND Phenotypic heterogeneity of melanoma cells contributes to drug tolerance, increased metastasis, and immune evasion in patients with progressive disease. Diverse mechanisms have been individually reported to shape extensive intra-tumor and inter-tumor phenotypic heterogeneity, such as IFNγ signaling and proliferative to invasive transition, but how their crosstalk impacts tumor progression remains largely elusive. METHODS Here, we integrate dynamical systems modeling with transcriptomic data analysis at bulk and single-cell levels to investigate underlying mechanisms behind phenotypic heterogeneity in melanoma and its impact on adaptation to targeted therapy and immune checkpoint inhibitors. We construct a minimal core regulatory network involving transcription factors implicated in this process and identify the multiple 'attractors' in the phenotypic landscape enabled by this network. Our model predictions about synergistic control of PD-L1 by IFNγ signaling and proliferative to invasive transition were validated experimentally in three melanoma cell lines-MALME3, SK-MEL-5 and A375. RESULTS We demonstrate that the emergent dynamics of our regulatory network comprising MITF, SOX10, SOX9, JUN and ZEB1 can recapitulate experimental observations about the co-existence of diverse phenotypes (proliferative, neural crest-like, invasive) and reversible cell-state transitions among them, including in response to targeted therapy and immune checkpoint inhibitors. These phenotypes have varied levels of PD-L1, driving heterogeneity in immunosuppression. This heterogeneity in PD-L1 can be aggravated by combinatorial dynamics of these regulators with IFNγ signaling. Our model predictions about changes in proliferative to invasive transition and PD-L1 levels as melanoma cells evade targeted therapy and immune checkpoint inhibitors were validated in multiple RNA-seq data sets from in vitro and in vivo experiments. CONCLUSION Our calibrated dynamical model offers a platform to test combinatorial therapies and provide rational avenues for the treatment of metastatic melanoma. This improved understanding of crosstalk among PD-L1 expression, proliferative to invasive transition and IFNγ signaling can be leveraged to improve the clinical management of therapy-resistant and metastatic melanoma.
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Affiliation(s)
| | - Sarthak Sahoo
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India
| | - Shibjyoti Debnath
- Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Jason A Somarelli
- Department of Medicine, Duke University, Durham, North Carolina, USA
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India
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Subhadarshini S, Sahoo S, Debnath S, Somarelli JA, Jolly MK. Dynamical modelling of proliferative-invasive plasticity and IFNγ signaling in melanoma reveals mechanisms of PD-L1 expression heterogeneity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.09.523355. [PMID: 37398358 PMCID: PMC10312429 DOI: 10.1101/2023.01.09.523355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Phenotypic heterogeneity of melanoma cells contributes to drug tolerance, increased metastasis, and immune evasion in patients with progressive disease. Diverse mechanisms have been individually reported to shape extensive intra- and inter-tumoral phenotypic heterogeneity, such as IFNγ signaling and proliferative to invasive transition, but how their crosstalk impacts tumor progression remains largely elusive. Here, we integrate dynamical systems modeling with transcriptomic data analysis at bulk and single-cell levels to investigate underlying mechanisms behind phenotypic heterogeneity in melanoma and its impact on adaptation to targeted therapy and immune checkpoint inhibitors. We construct a minimal core regulatory network involving transcription factors implicated in this process and identify the multiple "attractors" in the phenotypic landscape enabled by this network. Our model predictions about synergistic control of PD-L1 by IFNγ signaling and proliferative to invasive transition were validated experimentally in three melanoma cell lines - MALME3, SK-MEL-5 and A375. We demonstrate that the emergent dynamics of our regulatory network comprising MITF, SOX10, SOX9, JUN and ZEB1 can recapitulate experimental observations about the co-existence of diverse phenotypes (proliferative, neural crest-like, invasive) and reversible cell-state transitions among them, including in response to targeted therapy and immune checkpoint inhibitors. These phenotypes have varied levels of PD-L1, driving heterogeneity in immune-suppression. This heterogeneity in PD-L1 can be aggravated by combinatorial dynamics of these regulators with IFNγ signaling. Our model predictions about changes in proliferative to invasive transition and PD-L1 levels as melanoma cells evade targeted therapy and immune checkpoint inhibitors were validated in multiple data sets from in vitro and in vivo experiments. Our calibrated dynamical model offers a platform to test combinatorial therapies and provide rational avenues for the treatment of metastatic melanoma. This improved understanding of crosstalk among PD-L1 expression, proliferative to invasive transition and IFNγ signaling can be leveraged to improve the clinical management of therapy-resistant and metastatic melanoma.
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Affiliation(s)
| | - Sarthak Sahoo
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, 560012, India
| | | | | | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, 560012, India
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Wu W, Kong X, Jia Y, Jia Y, Ou W, Dai C, Li G, Gao R. An overview of PAX1: Expression, function and regulation in development and diseases. Front Cell Dev Biol 2022; 10:1051102. [PMID: 36393845 PMCID: PMC9649799 DOI: 10.3389/fcell.2022.1051102] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2023] Open
Abstract
Transcription factors play multifaceted roles in embryonic development and diseases. PAX1, a paired-box transcription factor, has been elucidated to play key roles in multiple tissues during embryonic development by extensive studies. Recently, an emerging role of PAX1 in cancers was clarified. Herein, we summarize the expression and functions of PAX1 in skeletal system and thymus development, as well as cancer biology and outline its cellular and molecular modes of action and the association of PAX1 mutation or dysregulation with human diseases, thus providing insights for the molecular basis of congenital diseases and cancers.
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Affiliation(s)
- Weiyin Wu
- Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital, School of medicine, Xiamen University, Xiamen, China
| | - Xiangjun Kong
- Department of Pharmacy, Xiang'an Hospital of Xiamen University, School of medicine, Xiamen University, Xiamen, China
| | - Yanhan Jia
- Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yihui Jia
- Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital, School of medicine, Xiamen University, Xiamen, China
| | - Weimei Ou
- Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital, School of medicine, Xiamen University, Xiamen, China
| | - Cuilian Dai
- Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital, School of medicine, Xiamen University, Xiamen, China
| | - Gang Li
- Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital, School of medicine, Xiamen University, Xiamen, China
| | - Rui Gao
- Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital, School of medicine, Xiamen University, Xiamen, China
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8
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Comparative role of SOX10 gene in the gliogenesis of central, peripheral, and enteric nervous systems. Differentiation 2022; 128:13-25. [DOI: 10.1016/j.diff.2022.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 09/10/2022] [Accepted: 09/19/2022] [Indexed: 11/17/2022]
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Qi J, Ma L, Guo W. Recent advances in the regulation mechanism of SOX10. J Otol 2022; 17:247-252. [PMID: 36249926 PMCID: PMC9547104 DOI: 10.1016/j.joto.2022.08.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 11/29/2022] Open
Abstract
Neural crest (NC) is the primitive neural structure in embryonic stage, which develops from ectodermal neural plate cells and epithelial cells. When the neural fold forms into neural tube, neural crest also forms a cord like structure above the neural tube and below the ectoderm. Neural crest cells (NCC) have strong migration and proliferation abilities. A number of tissue cells differentiate from neural crest cells, such as melanocytes, central and peripheral neurons, glial cells, craniofacial cells, osteoblasts, chondrocytes and smooth muscle cells. The migration and differentiation of neural crest cells are regulated by a gene network where a variety of genes, transcriptional factors, signal pathways and growth factors are involved.
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Affiliation(s)
- Jingcui Qi
- Department of Otorhinolaryngology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Long Ma
- PLA Rocket Force Characteristic Medical Center Department of Stomatology, China
| | - Weiwei Guo
- College of Otolaryngology Head and Neck Surgery, Chinese PLA General Hospital, Beijing 100853, China
- National Clinical Research Center for Otolaryngologic Diseases, Beijing, China
- Key Lab of Hearing Science, Ministry of Education, China
- Beijing Key Lab of Hearing Impairment for Prevention and Treatment, Beijing, China
- Corresponding author. College of Otolaryngology Head and Neck Surgery, Chinese PLA General Hospital, Beijing 100853, China.
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10
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Steele RE, Sanders R, Phillips HM, Bamforth SD. PAX Genes in Cardiovascular Development. Int J Mol Sci 2022; 23:7713. [PMID: 35887061 PMCID: PMC9324344 DOI: 10.3390/ijms23147713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/07/2022] [Accepted: 07/11/2022] [Indexed: 01/25/2023] Open
Abstract
The mammalian heart is a four-chambered organ with systemic and pulmonary circulations to deliver oxygenated blood to the body, and a tightly regulated genetic network exists to shape normal development of the heart and its associated major arteries. A key process during cardiovascular morphogenesis is the septation of the outflow tract which initially forms as a single vessel before separating into the aorta and pulmonary trunk. The outflow tract connects to the aortic arch arteries which are derived from the pharyngeal arch arteries. Congenital heart defects are a major cause of death and morbidity and are frequently associated with a failure to deliver oxygenated blood to the body. The Pax transcription factor family is characterised through their highly conserved paired box and DNA binding domains and are crucial in organogenesis, regulating the development of a wide range of cells, organs and tissues including the cardiovascular system. Studies altering the expression of these genes in murine models, notably Pax3 and Pax9, have found a range of cardiovascular patterning abnormalities such as interruption of the aortic arch and common arterial trunk. This suggests that these Pax genes play a crucial role in the regulatory networks governing cardiovascular development.
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Affiliation(s)
| | | | | | - Simon D. Bamforth
- Bioscience Institute, Faculty of Medical Sciences, Newcastle University, Centre for Life, Newcastle NE1 3BZ, UK; (R.E.S.); (R.S.); (H.M.P.)
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Chaves-Moreira D, Mitchell MA, Arruza C, Rawat P, Sidoli S, Nameki R, Reddy J, Corona RI, Afeyan LK, Klein IA, Ma S, Winterhoff B, Konecny GE, Garcia BA, Brady DC, Lawrenson K, Morin PJ, Drapkin R. The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17. Sci Signal 2022; 15:eabm2496. [PMID: 35380877 DOI: 10.1126/scisignal.abm2496] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PAX8 is a master transcription factor that is essential during embryogenesis and promotes neoplastic growth. It is expressed by the secretory cells lining the female reproductive tract, and its deletion during development results in atresia of reproductive tract organs. Nearly all ovarian carcinomas express PAX8, and its knockdown results in apoptosis of ovarian cancer cells. To explore the role of PAX8 in these tissues, we purified the PAX8 protein complex from nonmalignant fallopian tube cells and high-grade serous ovarian carcinoma cell lines. We found that PAX8 was a member of a large chromatin remodeling complex and preferentially interacted with SOX17, another developmental transcription factor. Depleting either PAX8 or SOX17 from cancer cells altered the expression of factors involved in angiogenesis and functionally disrupted tubule and capillary formation in cell culture and mouse models. PAX8 and SOX17 in ovarian cancer cells promoted the secretion of angiogenic factors by suppressing the expression of SERPINE1, which encodes a proteinase inhibitor with antiangiogenic effects. The findings reveal a non-cell-autonomous function of these transcription factors in regulating angiogenesis in ovarian cancer.
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Affiliation(s)
- Daniele Chaves-Moreira
- Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Biomedical Research Building II/III, Suite 1224, Philadelphia, PA 19104, USA
| | - Marilyn A Mitchell
- Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Biomedical Research Building II/III, Suite 1224, Philadelphia, PA 19104, USA
| | - Cristina Arruza
- Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Biomedical Research Building II/III, Suite 1224, Philadelphia, PA 19104, USA
| | - Priyanka Rawat
- Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Biomedical Research Building II/III, Suite 1224, Philadelphia, PA 19104, USA
| | - Simone Sidoli
- Epigenetics Institute, Department of Biochemistry and Biophysics, Smilow Center for Translational Research, University of Pennsylvania Perelman School of Medicine, Suite 9-124, Philadelphia, PA 19104, USA
| | - Robbin Nameki
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.,Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Jessica Reddy
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.,Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Rosario I Corona
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.,Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Lena K Afeyan
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.,Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Isaac A Klein
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Sisi Ma
- Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA
| | - Boris Winterhoff
- Department of Obstetrics, Gynecology and Women's Health, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Gottfried E Konecny
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Benjamin A Garcia
- Epigenetics Institute, Department of Biochemistry and Biophysics, Smilow Center for Translational Research, University of Pennsylvania Perelman School of Medicine, Suite 9-124, Philadelphia, PA 19104, USA
| | - Donita C Brady
- Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Biomedical Research Building II/III, Suite 612, Philadelphia, PA 19104, USA.,Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Biomedical Research Building II/III, Suite 612, Philadelphia, PA 19104, USA
| | - Kate Lawrenson
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.,Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Patrice J Morin
- Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Biomedical Research Building II/III, Suite 1224, Philadelphia, PA 19104, USA
| | - Ronny Drapkin
- Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Biomedical Research Building II/III, Suite 1224, Philadelphia, PA 19104, USA
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Román-Gil MS, Pozas J, Rosero-Rodríguez D, Chamorro-Pérez J, Ruiz-Granados Á, Caracuel IR, Grande E, Molina-Cerrillo J, Alonso-Gordoa T. Resistance to RET targeted therapy in Thyroid Cancer: Molecular basis and overcoming strategies. Cancer Treat Rev 2022; 105:102372. [DOI: 10.1016/j.ctrv.2022.102372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 12/07/2022]
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13
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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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14
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Chatterjee S, Karasaki KM, Fries LE, Kapoor A, Chakravarti A. A multi-enhancer RET regulatory code is disrupted in Hirschsprung disease. Genome Res 2021; 31:2199-2208. [PMID: 34782358 PMCID: PMC8647834 DOI: 10.1101/gr.275667.121] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 10/05/2021] [Indexed: 01/25/2023]
Abstract
The major genetic risk factors for Hirschsprung disease (HSCR) are three common polymorphisms within cis-regulatory elements (CREs) of the receptor tyrosine kinase gene RET, which reduce its expression during enteric nervous system (ENS) development. These risk variants attenuate binding of the transcription factors RARB, GATA2, and SOX10 to their cognate CREs, reduce RET gene expression, and dysregulate other ENS and HSCR genes in the RET-EDNRB gene regulatory network (GRN). Here, we use siRNA, ChIP, and CRISPR-Cas9 deletion analyses in the SK-N-SH cell line to ask how many additional HSCR-associated risk variants reside in RET CREs that affect its gene expression. We identify 22 HSCR-associated variants in candidate RET CREs, of which seven have differential allele-specific in vitro enhancer activity, and four of these seven affect RET gene expression; of these, two enhancers are bound by the transcription factor PAX3. We also show that deleting multiple variant-containing enhancers leads to synergistic effects on RET gene expression. These, coupled with our prior results, show that common sequence variants in at least 10 RET enhancers affect HSCR risk, seven with experimental evidence of affecting RET gene expression, extending the known RET-EDNRB GRN to reveal an extensive regulatory code modulating disease risk at a single gene.
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Affiliation(s)
- Sumantra Chatterjee
- Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York 10016, USA
- Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, New York 10016, USA
| | - Kameko M Karasaki
- Department of Biology, Johns Hopkins University, Baltimore, Maryland 21205, USA
| | - Lauren E Fries
- Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York 10016, USA
| | - Ashish Kapoor
- Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA
| | - Aravinda Chakravarti
- Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York 10016, USA
- Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, New York 10016, USA
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15
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Pingault V, Zerad L, Bertani-Torres W, Bondurand N. SOX10: 20 years of phenotypic plurality and current understanding of its developmental function. J Med Genet 2021; 59:105-114. [PMID: 34667088 PMCID: PMC8788258 DOI: 10.1136/jmedgenet-2021-108105] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/19/2021] [Indexed: 12/25/2022]
Abstract
SOX10 belongs to a family of 20 SRY (sex-determining region Y)-related high mobility group box-containing (SOX) proteins, most of which contribute to cell type specification and differentiation of various lineages. The first clue that SOX10 is essential for development, especially in the neural crest, came with the discovery that heterozygous mutations occurring within and around SOX10 cause Waardenburg syndrome type 4. Since then, heterozygous mutations have been reported in Waardenburg syndrome type 2 (Waardenburg syndrome type without Hirschsprung disease), PCWH or PCW (peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, with or without Hirschsprung disease), intestinal manifestations beyond Hirschsprung (ie, chronic intestinal pseudo-obstruction), Kallmann syndrome and cancer. All of these diseases are consistent with the regulatory role of SOX10 in various neural crest derivatives (melanocytes, the enteric nervous system, Schwann cells and olfactory ensheathing cells) and extraneural crest tissues (inner ear, oligodendrocytes). The recent evolution of medical practice in constitutional genetics has led to the identification of SOX10 variants in atypical contexts, such as isolated hearing loss or neurodevelopmental disorders, making them more difficult to classify in the absence of both a typical phenotype and specific expertise. Here, we report novel mutations and review those that have already been published and their functional consequences, along with current understanding of SOX10 function in the affected cell types identified through in vivo and in vitro models. We also discuss research options to increase our understanding of the origin of the observed phenotypic variability and improve the diagnosis and medical care of affected patients.
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Affiliation(s)
- Veronique Pingault
- Department of Embryology and Genetics of Malformations, INSERM UMR 1163, Université de Paris and Institut Imagine, Paris, France .,Service de Génétique des Maladies Rares, AP-HP, Hopital Necker-Enfants Malades, Paris, France
| | - Lisa Zerad
- Department of Embryology and Genetics of Malformations, INSERM UMR 1163, Université de Paris and Institut Imagine, Paris, France
| | - William Bertani-Torres
- Department of Embryology and Genetics of Malformations, INSERM UMR 1163, Université de Paris and Institut Imagine, Paris, France
| | - Nadege Bondurand
- Department of Embryology and Genetics of Malformations, INSERM UMR 1163, Université de Paris and Institut Imagine, Paris, France
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16
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Waardenburg syndrome type II in a Chinese pedigree caused by frameshift mutation in the SOX10 gene. Biosci Rep 2021; 41:227397. [PMID: 33345266 PMCID: PMC8217986 DOI: 10.1042/bsr20193375] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 12/15/2020] [Accepted: 12/18/2020] [Indexed: 01/21/2023] Open
Abstract
Waardenburg syndrome (WS) is a congenital hereditary disease, attributed to the most common symptoms of sensorineural deafness and iris hypopigmentation. It is also known as the hearing-pigmentation deficient syndrome. Mutations on SOXl0 gene often lead to congenital deafness and has been shown to play an important role in the pathogenesis of WS. We investigated one family of five members, with four patients exhibiting the classic form of WS2, whose DNA samples were analyzed by the technique of Whole-exome sequencing (WES). From analysis of WES data, we found that both the mother and all three children in the family have a heterozygous mutation on the Sex Determining Region Y - Box 10 (SOX10) gene. The mutation was c.298_300delinsGG in exon 2 of SOX10 (NM_006941), which leads to a frameshift of nine nucleotides, hence the amino acids (p. S100Rfs*9) are altered and the protein translation may be terminated prematurely. Further flow cytometry confirmed significant down-regulation of SOX10 protein, which indicated the SOX10 gene mutation was responsible for the pathogenesis of WS2 patients. In addition, we speculated that some other mutated genes might be related to disease phenotype in this family, which might also participate in promoting the progression of WS2.
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17
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Hosseini S, Schmitt AO, Tetens J, Brenig B, Simianer H, Sharifi AR, Gültas M. In Silico Prediction of Transcription Factor Collaborations Underlying Phenotypic Sexual Dimorphism in Zebrafish ( Danio rerio). Genes (Basel) 2021; 12:873. [PMID: 34200177 PMCID: PMC8227731 DOI: 10.3390/genes12060873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/02/2021] [Accepted: 06/05/2021] [Indexed: 11/17/2022] Open
Abstract
The transcriptional regulation of gene expression in higher organisms is essential for different cellular and biological processes. These processes are controlled by transcription factors and their combinatorial interplay, which are crucial for complex genetic programs and transcriptional machinery. The regulation of sex-biased gene expression plays a major role in phenotypic sexual dimorphism in many species, causing dimorphic gene expression patterns between two different sexes. The role of transcription factor (TF) in gene regulatory mechanisms so far has not been studied for sex determination and sex-associated colour patterning in zebrafish with respect to phenotypic sexual dimorphism. To address this open biological issue, we applied bioinformatics approaches for identifying the predicted TF pairs based on their binding sites for sex and colour genes in zebrafish. In this study, we identified 25 (e.g., STAT6-GATA4; JUN-GATA4; SOX9-JUN) and 14 (e.g., IRF-STAT6; SOX9-JUN; STAT6-GATA4) potentially cooperating TFs based on their binding patterns in promoter regions for sex determination and colour pattern genes in zebrafish, respectively. The comparison between identified TFs for sex and colour genes revealed several predicted TF pairs (e.g., STAT6-GATA4; JUN-SOX9) are common for both phenotypes, which may play a pivotal role in phenotypic sexual dimorphism in zebrafish.
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Affiliation(s)
- Shahrbanou Hosseini
- Molecular Biology of Livestock and Molecular Diagnostics Group, Department of Animal Sciences, University of Göttingen, 37077 Göttingen, Germany;
- Functional Breeding Group, Department of Animal Sciences, University of Göttingen, 37077 Göttingen, Germany;
- Institute of Veterinary Medicine, University of Göttingen, 37077 Göttingen, Germany
- Center for Integrated Breeding Research (CiBreed), University of Göttingen, 37075 Göttingen, Germany; (A.O.S.); (H.S.); (A.R.S.); (M.G.)
| | - Armin Otto Schmitt
- Center for Integrated Breeding Research (CiBreed), University of Göttingen, 37075 Göttingen, Germany; (A.O.S.); (H.S.); (A.R.S.); (M.G.)
- Breeding Informatics Group, Department of Animal Sciences, University of Göttingen, 37075 Göttingen, Germany
| | - Jens Tetens
- Functional Breeding Group, Department of Animal Sciences, University of Göttingen, 37077 Göttingen, Germany;
- Center for Integrated Breeding Research (CiBreed), University of Göttingen, 37075 Göttingen, Germany; (A.O.S.); (H.S.); (A.R.S.); (M.G.)
| | - Bertram Brenig
- Molecular Biology of Livestock and Molecular Diagnostics Group, Department of Animal Sciences, University of Göttingen, 37077 Göttingen, Germany;
- Institute of Veterinary Medicine, University of Göttingen, 37077 Göttingen, Germany
- Center for Integrated Breeding Research (CiBreed), University of Göttingen, 37075 Göttingen, Germany; (A.O.S.); (H.S.); (A.R.S.); (M.G.)
| | - Henner Simianer
- Center for Integrated Breeding Research (CiBreed), University of Göttingen, 37075 Göttingen, Germany; (A.O.S.); (H.S.); (A.R.S.); (M.G.)
- Animal Breeding and Genetics Group, Department of Animal Sciences, University of Göttingen, 37075 Göttingen, Germany
| | - Ahmad Reza Sharifi
- Center for Integrated Breeding Research (CiBreed), University of Göttingen, 37075 Göttingen, Germany; (A.O.S.); (H.S.); (A.R.S.); (M.G.)
- Animal Breeding and Genetics Group, Department of Animal Sciences, University of Göttingen, 37075 Göttingen, Germany
| | - Mehmet Gültas
- Center for Integrated Breeding Research (CiBreed), University of Göttingen, 37075 Göttingen, Germany; (A.O.S.); (H.S.); (A.R.S.); (M.G.)
- Breeding Informatics Group, Department of Animal Sciences, University of Göttingen, 37075 Göttingen, Germany
- Faculty of Agriculture, South Westphalia University of Applied Sciences, 59494 Soest, Germany
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18
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Gao T, Wright-Jin EC, Sengupta R, Anderson JB, Heuckeroth RO. Cell-autonomous retinoic acid receptor signaling has stage-specific effects on mouse enteric nervous system. JCI Insight 2021; 6:145854. [PMID: 33848271 PMCID: PMC8262371 DOI: 10.1172/jci.insight.145854] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 04/07/2021] [Indexed: 12/11/2022] Open
Abstract
Retinoic acid (RA) signaling is essential for enteric nervous system (ENS) development, since vitamin A deficiency or mutations in RA signaling profoundly reduce bowel colonization by ENS precursors. These RA effects could occur because of RA activity within the ENS lineage or via RA activity in other cell types. To define cell-autonomous roles for retinoid signaling within the ENS lineage at distinct developmental time points, we activated a potent floxed dominant-negative RA receptor α (RarαDN) in the ENS using diverse CRE recombinase–expressing mouse lines. This strategy enabled us to block RA signaling at premigratory, migratory, and postmigratory stages for ENS precursors. We found that cell-autonomous loss of RA receptor (RAR) signaling dramatically affected ENS development. CRE activation of RarαDN expression at premigratory or migratory stages caused severe intestinal aganglionosis, but at later stages, RarαDN induced a broad range of phenotypes including hypoganglionosis, submucosal plexus loss, and abnormal neural differentiation. RNA sequencing highlighted distinct RA-regulated gene sets at different developmental stages. These studies show complicated context-dependent RA-mediated regulation of ENS development.
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Affiliation(s)
- Tao Gao
- Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA
| | - Elizabeth C Wright-Jin
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Rajarshi Sengupta
- Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA
| | - Jessica B Anderson
- Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA
| | - Robert O Heuckeroth
- Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.,Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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19
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Fancelli S, Caliman E, Mazzoni F, Brugia M, Castiglione F, Voltolini L, Pillozzi S, Antonuzzo L. Chasing the Target: New Phenomena of Resistance to Novel Selective RET Inhibitors in Lung Cancer. Updated Evidence and Future Perspectives. Cancers (Basel) 2021; 13:cancers13051091. [PMID: 33806299 PMCID: PMC7961559 DOI: 10.3390/cancers13051091] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/13/2021] [Accepted: 02/26/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary REarranged during Transfection (RET) is an emerging target for several types of cancer, including non-small cell lung cancer (NSCLC). The recent U.S. FDA approval of pralsetinib and selpercatinib raises issues regarding the emergence of secondary mutations and amplifications involved in parallel signaling pathways and receptors, liable for resistance mechanisms. The aim of this review is to explore recent knowledge on RET resistance in NSCLC in pre-clinic and in clinical settings and accordingly, the state-of-the-art in new drugs or combination of drugs development. Abstract The potent, RET-selective tyrosine kinase inhibitors (TKIs) pralsetinib and selpercatinib, are effective against the RET V804L/M gatekeeper mutants, however, adaptive mutations that cause resistance at the solvent front RET G810 residue have been found, pointing to the need for the development of the next-generation of RET-specific TKIs. Also, as seen in EGFR- and ALK-driven NSCLC, the rising of the co-occurring amplifications of KRAS and MET could represent other escaping mechanisms from direct inhibition. In this review, we summarize actual knowledge on RET fusions, focusing on those involved in NSCLC, the results of main clinical trials of approved RET-inhibition drugs, with particular attention on recent published results of selective TKIs, and finally, pre-clinical evidence regarding resistance mechanisms and suggestion on hypothetical and feasible drugs combinations and strategies viable in the near future.
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Affiliation(s)
- Sara Fancelli
- Medical Oncology Unit, Careggi University Hospital, 50134 Florence, Italy; (S.F.); (E.C.); (F.M.); (M.B.); (S.P.)
| | - Enrico Caliman
- Medical Oncology Unit, Careggi University Hospital, 50134 Florence, Italy; (S.F.); (E.C.); (F.M.); (M.B.); (S.P.)
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy;
| | - Francesca Mazzoni
- Medical Oncology Unit, Careggi University Hospital, 50134 Florence, Italy; (S.F.); (E.C.); (F.M.); (M.B.); (S.P.)
| | - Marco Brugia
- Medical Oncology Unit, Careggi University Hospital, 50134 Florence, Italy; (S.F.); (E.C.); (F.M.); (M.B.); (S.P.)
| | - Francesca Castiglione
- Pathological Histology and Molecular Diagnostics Unit, Careggi University Hospital, 50134 Florence, Italy;
| | - Luca Voltolini
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy;
- Thoraco-Pulmonary Surgery Unit, Careggi University Hospital, 50134 Florence, Italy
| | - Serena Pillozzi
- Medical Oncology Unit, Careggi University Hospital, 50134 Florence, Italy; (S.F.); (E.C.); (F.M.); (M.B.); (S.P.)
| | - Lorenzo Antonuzzo
- Medical Oncology Unit, Careggi University Hospital, 50134 Florence, Italy; (S.F.); (E.C.); (F.M.); (M.B.); (S.P.)
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy;
- Correspondence: ; Tel.: +39-055-7948406
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20
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Perera SN, Williams RM, Lyne R, Stubbs O, Buehler DP, Sauka-Spengler T, Noda M, Micklem G, Southard-Smith EM, Baker CVH. Insights into olfactory ensheathing cell development from a laser-microdissection and transcriptome-profiling approach. Glia 2020; 68:2550-2584. [PMID: 32857879 PMCID: PMC7116175 DOI: 10.1002/glia.23870] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 05/23/2020] [Accepted: 05/27/2020] [Indexed: 12/14/2022]
Abstract
Olfactory ensheathing cells (OECs) are neural crest-derived glia that ensheath bundles of olfactory axons from their peripheral origins in the olfactory epithelium to their central targets in the olfactory bulb. We took an unbiased laser microdissection and differential RNA-seq approach, validated by in situ hybridization, to identify candidate molecular mechanisms underlying mouse OEC development and differences with the neural crest-derived Schwann cells developing on other peripheral nerves. We identified 25 novel markers for developing OECs in the olfactory mucosa and/or the olfactory nerve layer surrounding the olfactory bulb, of which 15 were OEC-specific (that is, not expressed by Schwann cells). One pan-OEC-specific gene, Ptprz1, encodes a receptor-like tyrosine phosphatase that blocks oligodendrocyte differentiation. Mutant analysis suggests Ptprz1 may also act as a brake on OEC differentiation, and that its loss disrupts olfactory axon targeting. Overall, our results provide new insights into OEC development and the diversification of neural crest-derived glia.
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Affiliation(s)
- Surangi N Perera
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Ruth M Williams
- MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Rachel Lyne
- Department of Genetics, University of Cambridge, Cambridge, UK
| | - Oliver Stubbs
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Dennis P Buehler
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Tatjana Sauka-Spengler
- MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Masaharu Noda
- Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki, Japan
| | - Gos Micklem
- Department of Genetics, University of Cambridge, Cambridge, UK
| | - E Michelle Southard-Smith
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Clare V H Baker
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
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21
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SOX10-regulated promoter use defines isoform-specific gene expression in Schwann cells. BMC Genomics 2020; 21:549. [PMID: 32770939 PMCID: PMC7430845 DOI: 10.1186/s12864-020-06963-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 07/29/2020] [Indexed: 01/12/2023] Open
Abstract
Background Multicellular organisms adopt various strategies to tailor gene expression to cellular contexts including the employment of multiple promoters (and the associated transcription start sites (TSSs)) at a single locus that encodes distinct gene isoforms. Schwann cells—the myelinating cells of the peripheral nervous system (PNS)—exhibit a specialized gene expression profile directed by the transcription factor SOX10, which is essential for PNS myelination. SOX10 regulates promoter elements associated with unique TSSs and gene isoforms at several target loci, implicating SOX10-mediated, isoform-specific gene expression in Schwann cell function. Here, we report on genome-wide efforts to identify SOX10-regulated promoters and TSSs in Schwann cells to prioritize genes and isoforms for further study. Results We performed global TSS analyses and mined previously reported ChIP-seq datasets to assess the activity of SOX10-bound promoters in three models: (i) an adult mammalian nerve; (ii) differentiating primary Schwann cells, and (iii) cultured Schwann cells with ablated SOX10 function. We explored specific characteristics of SOX10-dependent TSSs, which provides confidence in defining them as SOX10 targets. Finally, we performed functional studies to validate our findings at four previously unreported SOX10 target loci: ARPC1A, CHN2, DDR1, and GAS7. These findings suggest roles for the associated SOX10-regulated gene products in PNS myelination. Conclusions In sum, we provide comprehensive computational and functional assessments of SOX10-regulated TSS use in Schwann cells. The data presented in this study will stimulate functional studies on the specific mRNA and protein isoforms that SOX10 regulates, which will improve our understanding of myelination in the peripheral nerve.
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22
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Gattelli A, Hynes NE, Schor IE, Vallone SA. Ret Receptor Has Distinct Alterations and Functions in Breast Cancer. J Mammary Gland Biol Neoplasia 2020; 25:13-26. [PMID: 32080788 DOI: 10.1007/s10911-020-09445-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 02/06/2020] [Indexed: 12/15/2022] Open
Abstract
Ret receptor tyrosine kinase is a proto-oncogene that participates in development of various cancers. Several independent studies have recently identified Ret as a key player in breast cancer. Although Ret overexpression and function have been under investigation, mainly in estrogen receptor positive breast cancer, a more comprehensive analysis of the impact of recurring Ret alterations in breast cancer is needed. This review consolidates the current knowledge of Ret alterations and their potential effects in breast cancer. We discuss and integrate data on Ret changes in different breast cancer subtypes and potential function in progression, as well as the participation of distinct Ret network signaling partners in these processes. We propose that it will be essential to define a shared molecular feature of tumors with alteration in Ret receptor, be this at the genetic level or via overexpression in order to design effective therapies to target the Ret pathway. Here we review experimental evidence from basic research and pre-clinical studies concentrating on Ret alterations as potential biomarkers for recurrence, and we discuss the possibility that targeting the Ret pathway might in the future become a treatment for breast cancer.
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Affiliation(s)
- Albana Gattelli
- CONICET-UBA, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Ciudad Universitaria, C1428EGA CABA, Buenos Aires, Argentina.
- Universidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria C1428EGA CABA, Buenos Aires, Argentina.
| | - Nancy E Hynes
- Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, CH-4058, Basel, Switzerland
- University of Basel, CH-4002, Basel, Switzerland
| | - Ignacio E Schor
- CONICET-UBA, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Ciudad Universitaria, C1428EGA CABA, Buenos Aires, Argentina
- Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), Ciudad Universitaria, C1428EGA, CABA, Argentina
| | - Sabrina A Vallone
- CONICET-UBA, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Ciudad Universitaria, C1428EGA CABA, Buenos Aires, Argentina
- Universidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria C1428EGA CABA, Buenos Aires, Argentina
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23
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Park JS, Kim SM, Choi J, Jung KA, Hwang SH, Yang S, Kwok SK, Cho ML, Park SH. Interleukin-21-mediated suppression of the Pax3-Id3 pathway exacerbates the development of Sjögren's syndrome via follicular helper T cells. Cytokine 2019; 125:154834. [PMID: 31491724 DOI: 10.1016/j.cyto.2019.154834] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 08/26/2019] [Accepted: 08/27/2019] [Indexed: 11/26/2022]
Abstract
Sjögren's syndrome (SS) is a systemic autoimmune disease with severe dysfunction of glandular secretory function mediated by T and B lymphocyte infiltration into the exocrine glands, including the salivary and lacrimal glands. Follicular helper T (Tfh) cells exacerbate the disease by causing B cell hyperactivity. Inhibitor of DNA binding 3 (Id3) deficiency causes activation of Tfh cells and is known to be a clinical manifestation of human SS disease. In this study, we investigated the mechanism of action of Pax3, which is reduced in SS and can interact with Id3, in NOD/ShiLtJ mice as an animal model of SS. Treatment with interleukin (IL)-21, a major cytokine secreted from Tfh cells, suppressed Pax3 and Id3 expression via STAT3 in splenic T cells in vitro. Administration of pCMV14-3xFlag PAX3 vector improved the severity of SS by reducing the number of Tfh cells in NOD/ShiLtJ mice. Application of IL-21R-Fc increased the number of Pax3- and Id3-positive cells in the salivary glands, while reducing the proportion of Tfh cells and IL-17-producing T cells in NOD/ShiLtJ mice. The salivary glands from SS patients showed decreased levels of Pax3 or Id3 expression compared with healthy controls. Our findings regarding reinforcement of the Pax3-Id3 signal pathway may facilitate the development of novel therapeutic strategies for SS.
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Affiliation(s)
- Jin-Sil Park
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Sung-Min Kim
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - JeongWon Choi
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Kyung-Ah Jung
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Sun-Hee Hwang
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - SeungCheon Yang
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Seung-Ki Kwok
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Divison of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Mi-La Cho
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
| | - Sung-Hwan Park
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Divison of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
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Luzón‐Toro B, Villalba‐Benito L, Torroglosa A, Fernández RM, Antiñolo G, Borrego S. What is new about the genetic background of Hirschsprung disease? Clin Genet 2019; 97:114-124. [DOI: 10.1111/cge.13615] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/23/2019] [Accepted: 07/25/2019] [Indexed: 01/01/2023]
Affiliation(s)
- Berta Luzón‐Toro
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Leticia Villalba‐Benito
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Ana Torroglosa
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Raquel M. Fernández
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Guillermo Antiñolo
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Salud Borrego
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
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25
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Dai W, Wu J, Zhao Y, Jiang F, Zheng R, Chen DN, Men M, Li JD. Functional analysis of SOX10 mutations identified in Chinese patients with Kallmann syndrome. Gene 2019; 702:99-106. [DOI: 10.1016/j.gene.2019.03.039] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 03/15/2019] [Accepted: 03/19/2019] [Indexed: 12/20/2022]
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26
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Niego A, Benítez-Burraco A. Williams Syndrome, Human Self-Domestication, and Language Evolution. Front Psychol 2019; 10:521. [PMID: 30936846 PMCID: PMC6431629 DOI: 10.3389/fpsyg.2019.00521] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 02/22/2019] [Indexed: 01/06/2023] Open
Abstract
Language evolution resulted from changes in our biology, behavior, and culture. One source of these changes might be human self-domestication. Williams syndrome (WS) is a clinical condition with a clearly defined genetic basis which results in a distinctive behavioral and cognitive profile, including enhanced sociability. In this paper we show evidence that the WS phenotype can be satisfactorily construed as a hyper-domesticated human phenotype, plausibly resulting from the effect of the WS hemideletion on selected candidates for domestication and neural crest (NC) function. Specifically, we show that genes involved in animal domestication and NC development and function are significantly dysregulated in the blood of subjects with WS. We also discuss the consequences of this link between domestication and WS for our current understanding of language evolution.
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Affiliation(s)
- Amy Niego
- Ph.D. Program, Faculty of Humanities, University of Huelva, Huelva, Spain
| | - Antonio Benítez-Burraco
- Department of Spanish, Linguistics, and Theory of Literature, Faculty of Philology, University of Seville, Seville, Spain
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27
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Migration and diversification of the vagal neural crest. Dev Biol 2018; 444 Suppl 1:S98-S109. [PMID: 29981692 DOI: 10.1016/j.ydbio.2018.07.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 07/03/2018] [Accepted: 07/03/2018] [Indexed: 12/17/2022]
Abstract
Arising within the neural tube between the cranial and trunk regions of the body axis, the vagal neural crest shares interesting similarities in its migratory routes and derivatives with other neural crest populations. However, the vagal neural crest is also unique in its ability to contribute to diverse organs including the heart and enteric nervous system. This review highlights the migratory routes of the vagal neural crest and compares them across multiple vertebrates. We also summarize recent advances in understanding vagal neural crest ontogeny and discuss the contribution of this important neural crest population to the cardiovascular system and endoderm-derived organs, including the thymus, lungs and pancreas.
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28
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Khatami F, Tavangar SM. Multiple Endocrine Neoplasia Syndromes from Genetic and Epigenetic Perspectives. Biomark Insights 2018; 13:1177271918785129. [PMID: 30013307 PMCID: PMC6043927 DOI: 10.1177/1177271918785129] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 05/24/2018] [Indexed: 12/20/2022] Open
Abstract
Multiple endocrine neoplasia (MEN) syndromes are infrequent inherited disorders in which more than one endocrine glands develop noncancerous (benign) or cancerous (malignant) tumors or grow excessively without forming tumors. There are 3 famous and well-known forms of MEN syndromes (MEN 1, MEN 2A, and MEN 2B) and a newly documented one (MEN4). These syndromes are infrequent and occurred in all ages and both men and women. Usually, germ line mutations that can be resulted in neoplastic transformation of anterior pituitary, parathyroid glands, and pancreatic islets in addition to gastrointestinal tract can be an indicator for MEN1. The medullary thyroid cancer (MTC) in association with pheochromocytoma and/or multiple lesions of parathyroid glands with hyperparathyroidism can be pointer of MEN2 which can be subgrouped into the MEN 2A, MEN 2B, and familial MTC syndromes. There are no distinct biochemical markers that allow identification of familial versus nonfamilial forms of the tumors, but familial MTC usually happens at a younger age than sporadic MTC. The MEN1 gene (menin protein) is in charge of MEN 1 disease, CDNK1B for MEN 4, and RET proto-oncogene for MEN 2. The focus over the molecular targets can bring some hope for both diagnosis and management of MEN syndromes. In the current review, we look at this disease and responsible genes and their cell signaling pathway involved.
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Affiliation(s)
- Fatemeh Khatami
- Chronic Diseases Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Tavangar
- Chronic Diseases Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pathology, Doctor Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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29
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Boudjadi S, Chatterjee B, Sun W, Vemu P, Barr FG. The expression and function of PAX3 in development and disease. Gene 2018; 666:145-157. [PMID: 29730428 DOI: 10.1016/j.gene.2018.04.087] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 04/26/2018] [Accepted: 04/27/2018] [Indexed: 12/27/2022]
Abstract
The PAX3 gene encodes a member of the PAX family of transcription factors that is characterized by a highly conserved paired box motif. The PAX3 protein is a transcription factor consisting of an N-terminal DNA binding domain (containing a paired box and homeodomain) and a C-terminal transcriptional activation domain. This protein is expressed during development of skeletal muscle, central nervous system and neural crest derivatives, and regulates expression of target genes that impact on proliferation, survival, differentiation and motility in these lineages. Germline mutations of the murine Pax3 and human PAX3 genes cause deficiencies in these developmental lineages and result in the Splotch phenotype and Waardenburg syndrome, respectively. Somatic genetic rearrangements that juxtapose the PAX3 DNA binding domain to the transcriptional activation domain of other transcription factors deregulate PAX3 function and contribute to the pathogenesis of the soft tissue cancers alveolar rhabdomyosarcoma and biphenotypic sinonasal sarcoma. The wild-type PAX3 protein is also expressed in other cancers related to developmental lineages that normally express this protein and exerts phenotypic effects related to its normal developmental role.
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Affiliation(s)
- Salah Boudjadi
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA
| | | | - Wenyue Sun
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA
| | - Prasantha Vemu
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA
| | - Frederic G Barr
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
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30
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Hemmi A, Okamura K, Tazawa R, Abe Y, Hayashi M, Izumi S, Tohyama J, Shimomura Y, Hozumi Y, Suzuki T. Waardenburg syndrome type IIE in a Japanese patient caused by a novel non-frame-shift duplication mutation in the SOX10 gene. J Dermatol 2017; 45:e110-e111. [PMID: 29168219 DOI: 10.1111/1346-8138.14151] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Ami Hemmi
- Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Ken Okamura
- Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Ryushi Tazawa
- Bioscince Medical Research Center, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Yuko Abe
- Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Masahiro Hayashi
- Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Shuji Izumi
- Department of Otolaryngology, Head and Neck Surgery, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Jun Tohyama
- Bioscince Medical Research Center, Niigata University Medical and Dental Hospital, Niigata, Japan.,Department of Child Neurology, Nishi-Niigata Chuo National Hospital, Niigata, Japan
| | - Yutaka Shimomura
- Department of Dermatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Yutaka Hozumi
- Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Tamio Suzuki
- Department of Dermatology, Yamagata University Faculty of Medicine, Yamagata, Japan
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31
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Functional Role of Cyclin-Dependent Kinase 5 in the Regulation of Melanogenesis and Epidermal Structure. Sci Rep 2017; 7:13783. [PMID: 29062096 PMCID: PMC5653820 DOI: 10.1038/s41598-017-12567-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 07/12/2017] [Indexed: 01/08/2023] Open
Abstract
The mammalian integumentary system plays important roles in body homeostasis, and dysfunction of melanogenesis or epidermal development may lead to a variety of skin diseases, including melanoma. Skin pigmentation in humans and coat color in fleece-producing animals are regulated by many genes. Among them, microphthalmia-associated transcription factor (MITF) and paired-box 3 (PAX3) are at the top of the cascade and regulate activities of many important melanogenic enzymes. Here, we report for the first time that cyclin-dependent kinase 5 (Cdk5) is an essential regulator of MITF and PAX3. Cdk5 knockdown in mice causes a lightened coat color, a polarized distribution of melanin and hyperproliferation of basal keratinocytes. Reduced expression of Keratin 10 (K10) resulting from Cdk5 knockdown may be responsible for an abnormal epidermal structure. In contrast, overexpression of Cdk5 in sheep (Ovis aries) only produces brown patches on a white background, with no other observable abnormalities. Collectively, our findings show that Cdk5 has an important functional role in the regulation of melanin production and transportation and in normal development of the integumentary system.
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32
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Withdrawn: Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the "-Omics" Era. Endocr Rev 2017. [PMID: 27454361 DOI: 10.1210/er.2015-1045.2016.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamic-pituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3)substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery. (Endocrine Reviews 36: 603-621, 2015).
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33
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Di Zanni E, Adamo A, Belligni E, Lerone M, Martucciello G, Mattioli G, Pini Prato A, Ravazzolo R, Silengo M, Bachetti T, Ceccherini I. Common PHOX2B poly-alanine contractions impair RET gene transcription, predisposing to Hirschsprung disease. Biochim Biophys Acta Mol Basis Dis 2017; 1863:1770-1777. [PMID: 28433712 DOI: 10.1016/j.bbadis.2017.04.017] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2016] [Revised: 03/27/2017] [Accepted: 04/17/2017] [Indexed: 01/08/2023]
Abstract
HSCR is a congenital disorder of the enteric nervous system, characterized by the absence of neurons along a variable length of the gut resulting from loss-of-function RET mutations. Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by impaired response to hypercapnia and hypoxemia caused by heterozygous mutations of the PHOX2B gene, mostly polyalanine (polyA) expansions but also missense, nonsense, and frameshift mutations, while polyA contractions are common in the population and believed neutral. HSCR associated CCHS can present in patients carrying PHOX2B mutations. Indeed, RET expression is orchestrated by different transcriptional factors among which PHOX2B, thus suggesting its possible role in HSCR pathogenesis. Following the observation of HSCR patients carrying in frame trinucleotide deletions within the polyalanine stretch in exon 3 (polyA contractions), we have verified the hypothesis that these PHOX2B variants do reduce its transcriptional activity, likely resulting in a down-regulation of RET expression and, consequently, favouring the development of the HSCR phenotype. Using proper reporter constructs, we show here that the in vitro transactivation of the RET promoter by different HSCR-associated PHOX2B polyA variants has resulted significantly lower compared to the effect of PHOX2B wild type protein. In particular, polyA contractions do induce a reduced transactivation of the RET promoter, milder compared to the severe polyA expansions associated with CCHS+HSCR, and correlated with the length of the deleted trait, with a more pronounced effect when contractions are larger.
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Affiliation(s)
- Eleonora Di Zanni
- UOC Genetica Medica, Istituto Giannina Gaslini, 16148, Genova, Italy
| | - Annalisa Adamo
- UOC Genetica Medica, Istituto Giannina Gaslini, 16148, Genova, Italy
| | - Elga Belligni
- Dipartimento Scienze della Sanità Pubblica e Pediatriche, Università di Torino, Torino, Italy
| | - Margherita Lerone
- UOC Genetica Medica, Istituto Giannina Gaslini, 16148, Genova, Italy
| | - Giuseppe Martucciello
- UOC Chirurgia, Istituto Giannina Gaslini, 16148 Genova, Italy; DiNOGMI, University of Genova, Genova, Italy
| | | | | | - Roberto Ravazzolo
- UOC Genetica Medica, Istituto Giannina Gaslini, 16148, Genova, Italy; DiNOGMI, University of Genova, Genova, Italy
| | - Margherita Silengo
- Dipartimento Scienze della Sanità Pubblica e Pediatriche, Università di Torino, Torino, Italy
| | - Tiziana Bachetti
- UOC Genetica Medica, Istituto Giannina Gaslini, 16148, Genova, Italy
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Lorenzo PI, Juárez-Vicente F, Cobo-Vuilleumier N, García-Domínguez M, Gauthier BR. The Diabetes-Linked Transcription Factor PAX4: From Gene to Functional Consequences. Genes (Basel) 2017; 8:genes8030101. [PMID: 28282933 PMCID: PMC5368705 DOI: 10.3390/genes8030101] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 02/24/2017] [Accepted: 03/03/2017] [Indexed: 12/26/2022] Open
Abstract
Paired box 4 (PAX4) is a key factor in the generation of insulin producing β-cells during embryonic development. In adult islets, PAX4 expression is sequestered to a subset of β-cells that are prone to proliferation and more resistant to stress-induced apoptosis. The importance of this transcription factor for adequate pancreatic islets functionality has been manifested by the association of mutations in PAX4 with the development of diabetes, independently of its etiology. Overexpression of this factor in adult islets stimulates β-cell proliferation and increases their resistance to apoptosis. Additionally, in an experimental model of autoimmune diabetes, a novel immunomodulatory function for this factor has been suggested. Altogether these data pinpoint at PAX4 as an important target for novel regenerative therapies for diabetes treatment, aiming at the preservation of the remaining β-cells in parallel to the stimulation of their proliferation to replenish the β-cell mass lost during the progression of the disease. However, the adequate development of such therapies requires the knowledge of the molecular mechanisms controlling the expression of PAX4 as well as the downstream effectors that could account for PAX4 action.
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Affiliation(s)
- Petra I Lorenzo
- Pancreatic Islet Development and Regeneration Unit, Department of Cell Regeneration and Advanced Therapies, CABIMER (Junta de Andalucía-CSIC-Universidad de Sevilla-Universidad Pablo de Olavide), Calle Américo Vespucio, 24, 41092 Sevilla, Spain.
| | - Francisco Juárez-Vicente
- Cell differentiation Lab, Department of Cell Signaling and Dynamics, CABIMER (Junta de Andalucía-CSIC-Universidad de Sevilla-Universidad Pablo de Olavide), Calle Américo Vespucio, 24, 41092 Sevilla, Spain.
| | - Nadia Cobo-Vuilleumier
- Pancreatic Islet Development and Regeneration Unit, Department of Cell Regeneration and Advanced Therapies, CABIMER (Junta de Andalucía-CSIC-Universidad de Sevilla-Universidad Pablo de Olavide), Calle Américo Vespucio, 24, 41092 Sevilla, Spain.
| | - Mario García-Domínguez
- Cell differentiation Lab, Department of Cell Signaling and Dynamics, CABIMER (Junta de Andalucía-CSIC-Universidad de Sevilla-Universidad Pablo de Olavide), Calle Américo Vespucio, 24, 41092 Sevilla, Spain.
| | - Benoit R Gauthier
- Pancreatic Islet Development and Regeneration Unit, Department of Cell Regeneration and Advanced Therapies, CABIMER (Junta de Andalucía-CSIC-Universidad de Sevilla-Universidad Pablo de Olavide), Calle Américo Vespucio, 24, 41092 Sevilla, Spain.
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35
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Taylor CR, Montagne WA, Eisen JS, Ganz J. Molecular fingerprinting delineates progenitor populations in the developing zebrafish enteric nervous system. Dev Dyn 2016; 245:1081-1096. [PMID: 27565577 DOI: 10.1002/dvdy.24438] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 07/01/2016] [Accepted: 07/29/2016] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND To understand the basis of nervous system development, we must learn how multipotent progenitors generate diverse neuronal and glial lineages. We addressed this issue in the zebrafish enteric nervous system (ENS), a complex neuronal and glial network that regulates essential intestinal functions. Little is currently known about how ENS progenitor subpopulations generate enteric neuronal and glial diversity. RESULTS We identified temporally and spatially dependent progenitor subpopulations based on coexpression of three genes essential for normal ENS development: phox2bb, sox10, and ret. Our data suggest that combinatorial expression of these genes delineates three major ENS progenitor subpopulations, (1) phox2bb + /ret- /sox10-, (2) phox2bb + /ret + /sox10-, and (3) phox2bb + /ret + /sox10+, that reflect temporal progression of progenitor maturation during migration. We also found that differentiating zebrafish neurons maintain phox2bb and ret expression, and lose sox10 expression. CONCLUSIONS Our data show that zebrafish enteric progenitors constitute a heterogeneous population at both early and late stages of ENS development and suggest that marker gene expression is indicative of a progenitor's fate. We propose that a progenitor's expression profile reveals its developmental state: "younger" wave front progenitors express all three genes, whereas more mature progenitors behind the wave front selectively lose sox10 and/or ret expression, which may indicate developmental restriction. Developmental Dynamics 245:1081-1096, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Charlotte R Taylor
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR 97403-1254, USA
| | - William A Montagne
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR 97403-1254, USA
| | - Judith S Eisen
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR 97403-1254, USA
| | - Julia Ganz
- Institute of Neuroscience, 1254 University of Oregon, Eugene, OR 97403-1254, USA. .,Current address: Department of Integrative Biology, Michigan State University, East Lansing, MI 48824, USA.
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36
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Regulators of gene expression in Enteric Neural Crest Cells are putative Hirschsprung disease genes. Dev Biol 2016; 416:255-265. [DOI: 10.1016/j.ydbio.2016.06.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 05/17/2016] [Accepted: 06/02/2016] [Indexed: 11/21/2022]
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37
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Bondurand N, Southard-Smith EM. Mouse models of Hirschsprung disease and other developmental disorders of the enteric nervous system: Old and new players. Dev Biol 2016; 417:139-57. [PMID: 27370713 DOI: 10.1016/j.ydbio.2016.06.042] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 06/27/2016] [Accepted: 06/27/2016] [Indexed: 12/18/2022]
Abstract
Hirschsprung disease (HSCR, intestinal aganglionosis) is a multigenic disorder with variable penetrance and severity that has a general population incidence of 1/5000 live births. Studies using animal models have contributed to our understanding of the developmental origins of HSCR and the genetic complexity of this disease. This review summarizes recent progress in understanding control of enteric nervous system (ENS) development through analyses in mouse models. An overview of signaling pathways that have long been known to control the migration, proliferation and differentiation of enteric neural progenitors into and along the developing gut is provided as a framework for the latest information on factors that influence enteric ganglia formation and maintenance. Newly identified genes and additional factors beyond discrete genes that contribute to ENS pathology including regulatory sequences, miRNAs and environmental factors are also introduced. Finally, because HSCR has become a paradigm for complex oligogenic diseases with non-Mendelian inheritance, the importance of gene interactions, modifier genes, and initial studies on genetic background effects are outlined.
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Affiliation(s)
- Nadege Bondurand
- INSERM, U955, Equipe 6, F-94000 Creteil, France; Universite Paris-Est, UPEC, F-94000 Creteil, France.
| | - E Michelle Southard-Smith
- Vanderbilt University Medical Center, Department of Medicine, 2215 Garland Ave, Nashville, TN 37232, USA.
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Lopez AP, Kugelman JR, Garcia-Rivera J, Urias E, Salinas SA, Fernandez-Zapico ME, Llano M. The Structure-Specific Recognition Protein 1 Associates with Lens Epithelium-Derived Growth Factor Proteins and Modulates HIV-1 Replication. J Mol Biol 2016; 428:2814-31. [PMID: 27216501 DOI: 10.1016/j.jmb.2016.05.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 04/21/2016] [Accepted: 05/16/2016] [Indexed: 10/21/2022]
Abstract
The lens epithelium-derived growth factor p75 (LEDGF/p75) is a chromatin-bound protein essential for efficient lentiviral integration. Genome-wide studies have located LEDGF/p75 inside actively transcribed genes where it mediates lentiviral integration. Although its role in HIV-1 integration is clearly established, the role of LEDGF/p75-associated proteins in HIV-1 infection remains unexplored. Using protein-protein interaction assays, we demonstrated that LEDGF/p75 complexes with a chromatin-remodeling complex facilitates chromatin transcription (FACT), a heterodimer of the structure-specific recognition protein 1 (SSRP1) and the human homolog of suppressor of Ty 16 (hSpt16). Detailed analysis of the interaction of LEDGF/p75 with the FACT complex indicates that LEDGF/p75 interacts with SSRP1 in an hSpt16-independent manner that requires the PWWP domain of LEDGF proteins and the HMG domain of SSRP1. Functional characterizations demonstrate a LEDGF/p75-independent role of SSRP1 in the regulation of HIV-1 replication. shRNA-mediated partial knockdown of SSRP1 reduces HIV-1 infection, but not Murine Leukemia Virus, in human CD4(+) T cells. Similarly, SSRP1 knockdown affects infection by HIV-1-derived viruses that express genes from the viral LTR but not from an internal immediate-early CMV promoter, suggesting a role of SSRP1 in LTR-driven gene expression but not in viral DNA integration. Together, our data demonstrate for the first time the association of LEDGF proteins with the FACT complex and give further support to a role of SSRP1 in HIV-1 infection.
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Affiliation(s)
- Angelica P Lopez
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Jeffrey R Kugelman
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Jose Garcia-Rivera
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Eduardo Urias
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Sandra A Salinas
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA
| | | | - Manuel Llano
- Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968, USA.
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Enguix-Riego MV, Torroglosa A, Fernández RM, Moya-Jiménez MJ, de Agustín JC, Antiñolo G, Borrego S. Identification of different mechanisms leading to PAX6 down-regulation as potential events contributing to the onset of Hirschsprung disease. Sci Rep 2016; 6:21160. [PMID: 26879676 PMCID: PMC4754768 DOI: 10.1038/srep21160] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 01/08/2016] [Indexed: 12/11/2022] Open
Abstract
Hirschsprung disease (HSCR) is attributed to a failure of neural crest derived cells to migrate, proliferate, differentiate or survive in the bowel wall during embryonic Enteric Nervous System (ENS) development. This process requires a wide and complex variety of molecules and signaling pathways which are activated by transcription factors. In an effort to better understand the etiology of HSCR, we have designed a study to identify new transcription factors participating in different stages of the colonization process. A differential expression study has been performed on a set of transcription factors using Neurosphere-like bodies from both HSCR and control patients. Differential expression levels were found for CDYL, MEIS1, STAT3 and PAX6. A significantly lower expression level for PAX6 in HSCR patients, would suit with the finding of an over-representation of the larger tandem (AC)m(AG)n repeats within the PAX6 promoter in HSCR patients, with the subsequent loss of protein P300 binding. Alternatively, PAX6 is a target for DNMT3B-dependant methylation, a process already proposed as a mechanism with a role in HSCR. Such decrease in PAX6 expression may influence in the proper function of signaling pathways involved in ENS with the confluence of additional genetic factors to the manifestation of HSCR phenotype.
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Affiliation(s)
- María Valle Enguix-Riego
- Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain
| | - Ana Torroglosa
- Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain
| | - Raquel María Fernández
- Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain
| | - María José Moya-Jiménez
- Department of Pediatric Surgery, University Hospital Virgen del Rocío, Seville, 41013, Spain
| | - Juan Carlos de Agustín
- Department of Pediatric Surgery, General University Hospital Gregorio Marañon, Madrid, 28009, Spain
| | - Guillermo Antiñolo
- Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain
| | - Salud Borrego
- Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain
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Stamou MI, Cox KH, Crowley WF. Withdrawn: Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the "-Omics" Era. Endocr Rev 2016; 2016:4-22. [PMID: 27454361 PMCID: PMC6958992 DOI: 10.1210/er.2015-1045.2016.1.test] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 09/15/2015] [Indexed: 12/17/2022]
Abstract
The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamic-pituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3)substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery. (Endocrine Reviews 36: 603-621, 2015).
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Affiliation(s)
- M I Stamou
- Harvard National Center for Translational Research in Reproduction and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
| | - K H Cox
- Harvard National Center for Translational Research in Reproduction and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
| | - William F Crowley
- Harvard National Center for Translational Research in Reproduction and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
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Xiao Y, Luo J, Zhang F, Li J, Han Y, Zhang D, Wang M, Ma Y, Xu L, Bai X, Wang H. A novel mutation in PAX3 associated with Waardenburg syndrome type I in a Chinese family. Acta Otolaryngol 2016; 136:439-45. [PMID: 26824486 DOI: 10.3109/00016489.2015.1132846] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
CONCLUSION The novel compound heterozygous mutation in PAX3 was the key genetic reason for WS1 in this family, which was useful to the molecular diagnosis of WS1. PURPOSE Screening the pathogenic mutations in a four generation Chinese family with Waardenburg syndrome type I (WS1). METHODS WS1 was diagnosed in a 4-year-old boy according to the Waardenburg syndrome Consortium criteria. The detailed family history revealed four affected members in the family. Routine clinical, audiological examination, and ophthalmologic evaluation were performed on four affected and 10 healthy members in this family. The genetic analysis was conducted, including the targeted next-generation sequencing of 127 known deafness genes combined with Sanger sequencing, TA clone and bioinformatic analysis. RESULTS A novel compound heterozygous mutation c.[169_170insC;172_174delAAG] (p.His57ProfsX55) was identified in PAX3, which was co-segregated with WS1 in the Chinese family. This mutation was absent in the unaffected family members and 200 ethnicity-matched controls. The phylogenetic analysis and three-dimensional (3D) modeling of Pax3 protein further confirmed that the novel compound heterozygous mutation was pathogenic.
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Affiliation(s)
- Yun Xiao
- a Department of Otorhinolaryngology Head and Neck Surgery , Shandong Provincial Hospital Affiliated to Shandong University , Jinan , PR China
- b Shandong Provincial Key Laboratory of Otology , Jinan , PR China
| | - Jianfen Luo
- a Department of Otorhinolaryngology Head and Neck Surgery , Shandong Provincial Hospital Affiliated to Shandong University , Jinan , PR China
- b Shandong Provincial Key Laboratory of Otology , Jinan , PR China
| | - Fengguo Zhang
- a Department of Otorhinolaryngology Head and Neck Surgery , Shandong Provincial Hospital Affiliated to Shandong University , Jinan , PR China
- b Shandong Provincial Key Laboratory of Otology , Jinan , PR China
| | - Jianfeng Li
- a Department of Otorhinolaryngology Head and Neck Surgery , Shandong Provincial Hospital Affiliated to Shandong University , Jinan , PR China
- b Shandong Provincial Key Laboratory of Otology , Jinan , PR China
| | - Yuechen Han
- a Department of Otorhinolaryngology Head and Neck Surgery , Shandong Provincial Hospital Affiliated to Shandong University , Jinan , PR China
- b Shandong Provincial Key Laboratory of Otology , Jinan , PR China
| | - Daogong Zhang
- a Department of Otorhinolaryngology Head and Neck Surgery , Shandong Provincial Hospital Affiliated to Shandong University , Jinan , PR China
- b Shandong Provincial Key Laboratory of Otology , Jinan , PR China
| | - Mingming Wang
- a Department of Otorhinolaryngology Head and Neck Surgery , Shandong Provincial Hospital Affiliated to Shandong University , Jinan , PR China
- b Shandong Provincial Key Laboratory of Otology , Jinan , PR China
| | - Yalin Ma
- a Department of Otorhinolaryngology Head and Neck Surgery , Shandong Provincial Hospital Affiliated to Shandong University , Jinan , PR China
- b Shandong Provincial Key Laboratory of Otology , Jinan , PR China
| | - Lei Xu
- a Department of Otorhinolaryngology Head and Neck Surgery , Shandong Provincial Hospital Affiliated to Shandong University , Jinan , PR China
- b Shandong Provincial Key Laboratory of Otology , Jinan , PR China
| | - Xiaohui Bai
- a Department of Otorhinolaryngology Head and Neck Surgery , Shandong Provincial Hospital Affiliated to Shandong University , Jinan , PR China
- b Shandong Provincial Key Laboratory of Otology , Jinan , PR China
| | - Haibo Wang
- a Department of Otorhinolaryngology Head and Neck Surgery , Shandong Provincial Hospital Affiliated to Shandong University , Jinan , PR China
- b Shandong Provincial Key Laboratory of Otology , Jinan , PR China
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Bery A, Mérot Y, Rétaux S. Genes expressed in mouse cortical progenitors are enriched in Pax, Lhx, and Sox transcription factor putative binding sites. Brain Res 2015; 1633:37-51. [PMID: 26721689 DOI: 10.1016/j.brainres.2015.12.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 11/25/2015] [Accepted: 12/14/2015] [Indexed: 11/19/2022]
Abstract
Considerable progress has been made in the understanding of molecular and cellular mechanisms controlling the development of the mammalian cortex. The proliferative and neurogenic properties of cortical progenitors located in the ventricular germinal zone start being understood. Little is known however on the cis-regulatory control that finely tunes gene expression in these progenitors. Here, we undertook an in silico-based approach to address this question, followed by some functional validation. Using the Eurexpress database, we established a list of 30 genes specifically expressed in the cortical germinal zone, we selected mouse/human conserved non-coding elements (CNEs) around these genes and we performed motif-enrichment search in these CNEs. We found an over-representation of motifs corresponding to binding sites for Pax, Sox, and Lhx transcription factors, often found as pairs and located within 100bp windows. A small subset of CNEs (n=7) was tested for enhancer activity, by ex-vivo and in utero electroporation assays. Two showed strong enhancer activity in the germinal zone progenitors. Mutagenesis experiments on a selected CNE showed the functional importance of the Pax, Sox, and Lhx TFBS for conferring enhancer activity to the CNE. Overall, from a cis-regulatory viewpoint, our data suggest an input from Pax, Sox and Lhx transcription factors to orchestrate corticogenesis. These results are discussed with regards to the known functional roles of Pax6, Sox2 and Lhx2 in cortical development.
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Affiliation(s)
- Amandine Bery
- DECA Group, Institut des Neurosciences Paris-Saclay, Université Paris-Saclay, Université Paris-Sud, CNRS, UMR 9197, 91198 Gif-sur-Yvette, France.
| | - Yohann Mérot
- DECA Group, Institut des Neurosciences Paris-Saclay, Université Paris-Saclay, Université Paris-Sud, CNRS, UMR 9197, 91198 Gif-sur-Yvette, France
| | - Sylvie Rétaux
- DECA Group, Institut des Neurosciences Paris-Saclay, Université Paris-Saclay, Université Paris-Sud, CNRS, UMR 9197, 91198 Gif-sur-Yvette, France.
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Stamou MI, Cox KH, Crowley WF. Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the "-Omics" Era. Endocr Rev 2015; 36:603-21. [PMID: 26394276 PMCID: PMC4702497 DOI: 10.1210/er.2015-1045] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 09/15/2015] [Indexed: 12/23/2022]
Abstract
The neuroendocrine regulation of reproduction is an intricate process requiring the exquisite coordination of an assortment of cellular networks, all converging on the GnRH neurons. These neurons have a complex life history, migrating mainly from the olfactory placode into the hypothalamus, where GnRH is secreted and acts as the master regulator of the hypothalamic-pituitary-gonadal axis. Much of what we know about the biology of the GnRH neurons has been aided by discoveries made using the human disease model of isolated GnRH deficiency (IGD), a family of rare Mendelian disorders that share a common failure of secretion and/or action of GnRH causing hypogonadotropic hypogonadism. Over the last 30 years, research groups around the world have been investigating the genetic basis of IGD using different strategies based on complex cases that harbor structural abnormalities or single pleiotropic genes, endogamous pedigrees, candidate gene approaches as well as pathway gene analyses. Although such traditional approaches, based on well-validated tools, have been critical to establish the field, new strategies, such as next-generation sequencing, are now providing speed and robustness, but also revealing a surprising number of variants in known IGD genes in both patients and healthy controls. Thus, before the field moves forward with new genetic tools and continues discovery efforts, we must reassess what we know about IGD genetics and prepare to hold our work to a different standard. The purpose of this review is to: 1) look back at the strategies used to discover the "known" genes implicated in the rare forms of IGD; 2) examine the strengths and weaknesses of the methodologies used to validate genetic variation; 3) substantiate the role of known genes in the pathophysiology of the disease; and 4) project forward as we embark upon a widening use of these new and powerful technologies for gene discovery.
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Affiliation(s)
- M I Stamou
- Harvard National Center for Translational Research in Reproduction and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
| | - K H Cox
- Harvard National Center for Translational Research in Reproduction and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
| | - William F Crowley
- Harvard National Center for Translational Research in Reproduction and Infertility, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
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Kubic JD, Little EC, Kaiser RS, Young KP, Lang D. FOXD3 Promotes PAX3 Expression in Melanoma Cells. J Cell Biochem 2015; 117:533-41. [PMID: 26252164 DOI: 10.1002/jcb.25306] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 08/04/2015] [Indexed: 01/01/2023]
Abstract
Several key transcription factors regulate cell growth, survival, and differentiation during neural crest and melanoblast development in the embryo, and these same pathways may be reactivated in tumors arising from the progenitors of these cells. The transcription factors PAX3 and FOXD3 have essential roles in melanoblasts and melanoma. In this study, we define a regulatory pathway where FOXD3 promotes the expression of PAX3. Both factors are expressed in melanoma cells and there is a positive correlation between the transcript levels of PAX3 and FOXD3. The PAX3 gene contains two FOX binding motifs within highly conserved enhancer regulatory elements that are essential for neural crest development. FOXD3 binds to both of these motifs in vitro but only one of these sites is preferentially utilized in melanoma cells. Overexpression of FOXD3 upregulates PAX3 levels while inhibition of FOXD3 function does not alter PAX3 protein levels, supporting that FOXD3 is sufficient but not necessary to drive PAX3 expression in melanoma cells. Here, we identify a molecular pathway where FOXD3 upregulates PAX3 expression and therefore contributes to melanoma progression.
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Affiliation(s)
- Jennifer D Kubic
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Illinois, 60637
| | - Elizabeth C Little
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Illinois, 60637
| | - Rebecca S Kaiser
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Illinois, 60637
| | - Kacey P Young
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Illinois, 60637
| | - Deborah Lang
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Illinois, 60637
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45
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Kubic JD, Lui JW, Little EC, Ludvik AE, Konda S, Salgia R, Aplin AE, Lang D. PAX3 and FOXD3 Promote CXCR4 Expression in Melanoma. J Biol Chem 2015. [PMID: 26205821 DOI: 10.1074/jbc.m115.670976] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Metastatic melanoma is an aggressive and deadly disease. The chemokine receptor CXCR4 is active in melanoma metastasis, although the mechanism for the promotion and maintenance of CXCR4 expression in these cells is mostly unknown. Here, we find melanoma cells express two CXCR4 isoforms, the common version and a variant that is normally restricted to cells during development or to mature blood cells. CXCR4 expression is driven through a highly conserved intronic enhancer element by the transcription factors PAX3 and FOXD3. Inhibition of these transcription factors slows melanoma cell growth, migration, and motility, as well as reduces CXCR4 expression. Overexpression of these transcription factors drives the production of increased CXCR4 levels. Loss of PAX3 and FOXD3 transcription factor activity results in a reduction in cell motility, migration, and chemotaxis, all of which are rescued by CXCR4 overexpression. Here, we discover a molecular pathway wherein PAX3 and FOXD3 promote CXCR4 gene expression in melanoma.
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Affiliation(s)
| | - Jason W Lui
- From the Department of Medicine, Section of Dermatology and
| | | | - Anton E Ludvik
- From the Department of Medicine, Section of Dermatology and
| | - Sasank Konda
- From the Department of Medicine, Section of Dermatology and
| | - Ravi Salgia
- Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637 and
| | - Andrew E Aplin
- the Department of Cancer Biology and Kimmel Cancer Center, and Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
| | - Deborah Lang
- From the Department of Medicine, Section of Dermatology and
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McCoy CR, Stadelman BS, Brumaghim JL, Liu JT, Bain LJ. Arsenic and Its Methylated Metabolites Inhibit the Differentiation of Neural Plate Border Specifier Cells. Chem Res Toxicol 2015; 28:1409-21. [PMID: 26024302 DOI: 10.1021/acs.chemrestox.5b00036] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Exposure to arsenic in food and drinking water has been correlated with adverse developmental outcomes, such as reductions in birth weight and neurological deficits. Additionally, studies have shown that arsenic suppresses sensory neuron formation and skeletal muscle myogenesis, although the reason why arsenic targets both of these cell types in unclear. Thus, P19 mouse embryonic stem cells were used to investigate the mechanisms by which arsenic could inhibit cellular differentiation. P19 cells were exposed to 0, 0.1, or 0.5 μM sodium arsenite and induced to form embryoid bodies over a period of 5 days. The expression of transcription factors necessary to form neural plate border specifier (NPBS) cells, neural crest cells and their progenitors, and myocytes and their progenitors were examined. Early during differentiation, arsenic significantly reduced the transcript and protein expression of Msx1 and Pax3, both needed for NPBS cell formation. Arsenic also significantly reduced the protein expression of Sox 10, needed for neural crest progenitor cell production, by 31-50%, and downregulated the protein and mRNA levels of NeuroD1, needed for neural crest cell differentiation, in a time- and dose-dependent manner. While the overall protein expression of transcription factors in the skeletal muscle lineage was not changed, arsenic did alter their nuclear localization. MyoD nuclear translocation was significantly reduced on days 2-5 between 15 and 70%. At a 10-fold lower concentration, monomethylarsonous acid (MMA III) appeared to be just as potent as inorganic arsenic at reducing the mRNA levels Pax3 (79% vs84%), Sox10 (49% vs 65%), and Msx1 (56% vs 56%). Dimethylarsinous acid (DMA III) also reduced protein and transcript expression, but the changes were less dramatic than those with MMA or arsenite. All three arsenic species reduced the nuclear localization of MyoD and NeuroD1 in a similar manner. The early changes in the differentiation of neural plate border specifier cells may provide a mechanism for arsenic to suppress both neurogenesis and myogenesis.
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Affiliation(s)
- Christopher R McCoy
- †Department of Biological Sciences, Clemson University, 132 Long Hall, Clemson, South Carolina 29634, United States
| | - Bradley S Stadelman
- ‡Department of Chemistry, Clemson University, 219 Hunter Laboratories, Clemson, South Carolina 29634, United States
| | - Julia L Brumaghim
- ‡Department of Chemistry, Clemson University, 219 Hunter Laboratories, Clemson, South Carolina 29634, United States
| | - Jui-Tung Liu
- §Environmental Toxicology Graduate Program, Clemson University, 132 Long Hall, Clemson, South Carolina 29634, United States
| | - Lisa J Bain
- †Department of Biological Sciences, Clemson University, 132 Long Hall, Clemson, South Carolina 29634, United States.,§Environmental Toxicology Graduate Program, Clemson University, 132 Long Hall, Clemson, South Carolina 29634, United States
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Chaoui A, Kavo A, Baral V, Watanabe Y, Lecerf L, Colley A, Mendoza-Londono R, Pingault V, Bondurand N. Subnuclear re-localization of SOX10 and p54NRB correlates with a unique neurological phenotype associated with SOX10 missense mutations. Hum Mol Genet 2015; 24:4933-47. [PMID: 26060192 DOI: 10.1093/hmg/ddv215] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 06/04/2015] [Indexed: 11/12/2022] Open
Abstract
SOX10 is a transcription factor with well-known functions in neural crest and oligodendrocyte development. Mutations in SOX10 were first associated with Waardenburg-Hirschsprung disease (WS4; deafness, pigmentation defects and intestinal aganglionosis). However, variable phenotypes that extend beyond the WS4 definition are now reported. The neurological phenotypes associated with some truncating mutations are suggested to be the result of escape from the nonsense-mediated mRNA decay pathway; but, to date, no mechanism has been suggested for missense mutations, of which approximately 20 have now been reported, with about half of the latter shown to be redistributed to nuclear bodies of undetermined nature and function in vitro. Here, we report that p54NRB, which plays a crucial role in the regulation of gene expression during many cellular processes including differentiation, interacts synergistically with SOX10 to regulate several target genes. Interestingly, this paraspeckle protein, as well as two other members of the Drosophila behavior human splicing (DBHS) protein family, co-localize with SOX10 mutants in nuclear bodies, suggesting the possible paraspeckle nature of these foci or re-localization of the DBHS members to other subnuclear compartments. Remarkably, the co-transfection of wild-type and mutant SOX10 constructs led to the sequestration of wild-type protein in mutant-induced foci. In contrast to mutants presenting with additional cytoplasmic re-localization, those exclusively found in the nucleus alter synergistic activity between SOX10 and p54NRB. We propose that such a dominant negative effect may contribute to or be at the origin of the unique progressive and severe neurological phenotype observed in affected patients.
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Affiliation(s)
- Asma Chaoui
- INSERM, U955, Equipe 6, 51 Avenue du Maréchal de Lattre de Tassigny, F-94000 Créteil, France, Université Paris-Est, UPEC, F-94000 Créteil, France, DHU Ageing-Thorax-Vessel-Blood, F-94000 Créteil, France
| | - Anthula Kavo
- INSERM, U955, Equipe 6, 51 Avenue du Maréchal de Lattre de Tassigny, F-94000 Créteil, France, Université Paris-Est, UPEC, F-94000 Créteil, France, DHU Ageing-Thorax-Vessel-Blood, F-94000 Créteil, France
| | - Viviane Baral
- INSERM, U955, Equipe 6, 51 Avenue du Maréchal de Lattre de Tassigny, F-94000 Créteil, France, Université Paris-Est, UPEC, F-94000 Créteil, France, DHU Ageing-Thorax-Vessel-Blood, F-94000 Créteil, France
| | - Yuli Watanabe
- INSERM, U955, Equipe 6, 51 Avenue du Maréchal de Lattre de Tassigny, F-94000 Créteil, France, Université Paris-Est, UPEC, F-94000 Créteil, France, DHU Ageing-Thorax-Vessel-Blood, F-94000 Créteil, France
| | - Laure Lecerf
- INSERM, U955, Equipe 6, 51 Avenue du Maréchal de Lattre de Tassigny, F-94000 Créteil, France, Université Paris-Est, UPEC, F-94000 Créteil, France, DHU Ageing-Thorax-Vessel-Blood, F-94000 Créteil, France
| | - Alison Colley
- Department of Clinical Genetics, Liverpool Hospital, Australia and
| | - Roberto Mendoza-Londono
- Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Canada
| | - Veronique Pingault
- INSERM, U955, Equipe 6, 51 Avenue du Maréchal de Lattre de Tassigny, F-94000 Créteil, France, Université Paris-Est, UPEC, F-94000 Créteil, France, DHU Ageing-Thorax-Vessel-Blood, F-94000 Créteil, France
| | - Nadege Bondurand
- INSERM, U955, Equipe 6, 51 Avenue du Maréchal de Lattre de Tassigny, F-94000 Créteil, France, Université Paris-Est, UPEC, F-94000 Créteil, France, DHU Ageing-Thorax-Vessel-Blood, F-94000 Créteil, France,
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48
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Huang J, Dang R, Torigoe D, Lei C, Lan X, Chen H, Sasaki N, Wang J, Agui T. Identification of genetic loci affecting the severity of symptoms of Hirschsprung disease in rats carrying Ednrbsl mutations by quantitative trait locus analysis. PLoS One 2015; 10:e0122068. [PMID: 25790447 PMCID: PMC4366197 DOI: 10.1371/journal.pone.0122068] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 02/12/2015] [Indexed: 01/17/2023] Open
Abstract
Hirschsprung’s disease (HSCR) is a congenital disease in neonates characterized by the absence of the enteric ganglia in a variable length of the distal colon. This disease results from multiple genetic interactions that modulate the ability of enteric neural crest cells to populate developing gut. We previously reported that three rat strains with different backgrounds (susceptible AGH-Ednrbsl/sl, resistant F344-Ednrbsl/sl, and LEH-Ednrbsl/sl) but the same null mutation of Ednrb show varying severity degrees of aganglionosis. This finding suggests that strain-specific genetic factors affect the severity of HSCR. Consistent with this finding, a quantitative trait locus (QTL) for the severity of HSCR on chromosome (Chr) 2 was identified using an F2 intercross between AGH and F344 strains. In the present study, we performed QTL analysis using an F2 intercross between the susceptible AGH and resistant LEH strains to identify the modifier/resistant loci for HSCR in Ednrb-deficient rats. A significant locus affecting the severity of HSCR was also detected within the Chr 2 region. These findings strongly suggest that a modifier gene of aganglionosis exists on Chr 2. In addition, two potentially causative SNPs (or mutations) were detected upstream of a known HSCR susceptibility gene, Gdnf. These SNPs were possibly responsible for the varied length of gut affected by aganglionosis.
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Affiliation(s)
- Jieping Huang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Ruihua Dang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
- * E-mail: (RD); (CL)
| | - Daisuke Torigoe
- Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan
| | - Chuzhao Lei
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
- * E-mail: (RD); (CL)
| | - Xianyong Lan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Hong Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Nobuya Sasaki
- Laboratory of Laboratory Animal Science and Medicine, School of Veterinary Medicine, Kitasato University, Aomori, Japan
| | - Jinxi Wang
- Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan
| | - Takashi Agui
- Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan
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49
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Narasimhan K, Pillay S, Huang YH, Jayabal S, Udayasuryan B, Veerapandian V, Kolatkar P, Cojocaru V, Pervushin K, Jauch R. DNA-mediated cooperativity facilitates the co-selection of cryptic enhancer sequences by SOX2 and PAX6 transcription factors. Nucleic Acids Res 2015; 43:1513-28. [PMID: 25578969 PMCID: PMC4330359 DOI: 10.1093/nar/gku1390] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Sox2 and Pax6 are transcription factors that direct cell fate decision during neurogenesis, yet the mechanism behind how they cooperate on enhancer DNA elements and regulate gene expression is unclear. By systematically interrogating Sox2 and Pax6 interaction on minimal enhancer elements, we found that cooperative DNA recognition relies on combinatorial nucleotide switches and precisely spaced, but cryptic composite DNA motifs. Surprisingly, all tested Sox and Pax paralogs have the capacity to cooperate on such enhancer elements. NMR and molecular modeling reveal very few direct protein-protein interactions between Sox2 and Pax6, suggesting that cooperative binding is mediated by allosteric interactions propagating through DNA structure. Furthermore, we detected and validated several novel sites in the human genome targeted cooperatively by Sox2 and Pax6. Collectively, we demonstrate that Sox-Pax partnerships have the potential to substantially alter DNA target specificities and likely enable the pleiotropic and context-specific action of these cell-lineage specifiers.
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Affiliation(s)
- Kamesh Narasimhan
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
| | - Shubhadra Pillay
- Genome Regulation Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China
| | - Yong-Heng Huang
- Laboratory for Structural Biochemistry, Genome Institute of Singapore, Singapore 138672, Singapore
| | - Sriram Jayabal
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada Integrated Program in Neuroscience, McGill University, Montreal, Quebec H3G 0B1, Canada
| | - Barath Udayasuryan
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada
| | - Veeramohan Veerapandian
- Laboratory for Structural Biochemistry, Genome Institute of Singapore, Singapore 138672, Singapore University of Chinese Academy of Sciences, No. 19A Yuquanlu, Beijing 100049, China
| | - Prasanna Kolatkar
- Qatar Biomedical Research Institute, Qatar Foundation, PO Box 5825, Doha, Qatar
| | - Vlad Cojocaru
- Computational Structural Biology Laboratory, Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster 48149, Germany
| | - Konstantin Pervushin
- Genome Regulation Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China
| | - Ralf Jauch
- Laboratory for Structural Biochemistry, Genome Institute of Singapore, Singapore 138672, Singapore
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50
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Fujiwara S, Hoshikawa S, Ueno T, Hirata M, Saito T, Ikeda T, Kawaguchi H, Nakamura K, Tanaka S, Ogata T. SOX10 transactivates S100B to suppress Schwann cell proliferation and to promote myelination. PLoS One 2014; 9:e115400. [PMID: 25536222 PMCID: PMC4275212 DOI: 10.1371/journal.pone.0115400] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 11/21/2014] [Indexed: 01/28/2023] Open
Abstract
Schwann cells are an important cell source for regenerative therapy for neural disorders. We investigated the role of the transcription factor sex determining region Y (SRY)-box 10 (SOX10) in the proliferation and myelination of Schwann cells. SOX10 is predominantly expressed in rat sciatic nerve-derived Schwann cells and is induced shortly after birth. Among transcription factors known to be important for the differentiation of Schwann cells, SOX10 potently transactivates the S100B promoter. In cultures of Schwann cells, overexpressing SOX10 dramatically induces S100B expression, while knocking down SOX10 with shRNA suppresses S100B expression. Here, we identify three core response elements of SOX10 in the S100B promoter and intron 1 with a putative SOX motif. Knockdown of either SOX10 or S100B enhances the proliferation of Schwann cells. In addition, using dissociated cultures of dorsal root ganglia, we demonstrate that suppressing S100B with shRNA impairs myelination of Schwann cells. These results suggest that the SOX10-S100B signaling axis critically regulates Schwann cell proliferation and myelination, and therefore is a putative therapeutic target for neuronal disorders.
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Affiliation(s)
- Sayaka Fujiwara
- Departments of Sensory & Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Shinya Hoshikawa
- Departments of Sensory & Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Takaaki Ueno
- Departments of Sensory & Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Makoto Hirata
- Departments of Sensory & Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Taku Saito
- Bone and Cartilage Regenerative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Toshiyuki Ikeda
- Departments of Sensory & Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Hiroshi Kawaguchi
- Departments of Sensory & Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Kozo Nakamura
- Departments of Sensory & Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Sakae Tanaka
- Departments of Sensory & Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Toru Ogata
- Department of Rehabilitation for the Movement Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities, Saitama, Japan
- * E-mail:
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