ArticleHuman molecular genetics2015
SRY interference of normal regulation of the RET gene suggests a potential role of the Y-chromosome gene in sexual dimorphism in Hirschsprung disease.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 23 citations in OpenAlex.
- A collagen VI-dependent pathogenic mechanism for Hirschsprung's disease.The Journal of clinical investigation · 2015Trial
- Proteomic Analysis Provides a New Sight Into the CRABP1 Expression in the Pathogenesis of Hirschsprung Disease.Biochemical genetics · 2025Article
- Sex-limited chromosomes and non-reproductive traits.BMC biology · 2022Review
- Genetic Regulation of Vertebrate Forebrain Development by Homeobox Genes.Frontiers in neuroscience · 2022Review
- Male-biased aganglionic megacolon in the TashT mouse model of Hirschsprung disease involves upregulation of p53 protein activity and Ddx3y gene expression.PLoS genetics · 2020Article
- Potential dual functional roles of the Y-linked RBMY in hepatocarcinogenesis.Cancer science · 2020Article
- Food, microbes, sex and old age: on the plasticity of gastrointestinal innervation.Current opinion in neurobiology · 2020Review
- Y chromosome in health and diseases.Cell & bioscience · 2020Review
- Hirschsprung disease - integrating basic science and clinical medicine to improve outcomes.Nature reviews. Gastroenterology & hepatology · 2018Review
- X chromosome dosage and presence of SRY shape sex-specific differences in DNA methylation at an autosomal region in human cells.Biology of sex differences · 2018Article
- Alteration of the Retinoid Acid-CBP Signaling Pathway in Neural Crest Induction Contributes to Enteric Nervous System Disorder.Frontiers in pediatrics · 2018Article
- Aberrant activation of the human sex-determining gene in early embryonic development results in postnatal growth retardation and lethality in mice.Scientific reports · 2017Article
- Exome-Wide Association Study Identified New Risk Loci for Hirschsprung's Disease.Molecular neurobiology · 2017Article
- Hirschsprung's disease: clinical dysmorphology, genes, micro-RNAs, and future perspectives.Pediatric research · 2017Review
- A Novel Zebrafish ret Heterozygous Model of Hirschsprung Disease Identifies a Functional Role for mapk10 as a Modifier of Enteric Nervous System Phenotype Severity.PLoS genetics · 2016Article
- Stress, sex, and the enteric nervous system.Neurogastroenterology and motility · 2016Review
- Chromosome Y genetic variants: impact in animal models and on human disease.Physiological genomics · 2015Review
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Authors and funding
6 authors at 4 institutions in 3 countries.
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Abstract
The Hirschsprung disease (HSCR) is a complex congenital disorder, arising from abnormalities in enteric nervous system (ENS) development. There is a gender disparity among the patients, with the male to female ratio as high as 5 : 1. Loss-of-function mutations of HSCR genes and haploinsufficiency of their gene products are the primary pathogenic mechanisms for disease development. Recent studies identified over half of the HSCR disease susceptibility genes as targets for the sex-determining factor SRY, suggesting that this Y-encoded transcription factor could be involved in sexual dimorphism in HSCR. Among the SRY targets, the tyrosine kinase receptor RET represents the most important disease gene, whose mutations account for half of the familial and up to one-third of the sporadic forms of HSCR. RET is regulated by a distal and a proximal enhancer at its promoter, in which PAX3 and NKX2-1 are the resident transcription factors respectively. We show that the SRY-box 10 (SOX10) co-activator interacts and forms transcriptional complexes with PAX3 and NKX2-1 in a sequence-independent manner and exacerbates their respective transactivation activities on the RET promoter. SRY competitively displaces SOX10 in such transcription complexes and represses their regulatory functions on RET. Hence SRY could be a Y-located negative modifier of RET expression; and if it is ectopically expressed during ENS development, such SRY repression could result in RET protein haploinsufficiency and promotion of HSCR development, thereby contributing to sexual dimorphism in HSCR.
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