title: SRY interference of normal regulation of the RET gene suggests a potential role of the Y-chromosome gene in sexual dimorphism in Hirschsprung disease.
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.
authors.affiliation: Department of Medicine Institute for Human Genetics, University of California, San Francisco, USA and.
authors.forename: Yunmin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicine Institute for Human Genetics, University of California, San Francisco, USA and.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kido
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, The University of Hong Kong, Hong Kong, China.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Garcia-Barcelo
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, The University of Hong Kong, Hong Kong, China.
authors.forename: Paul K H
authors.initials: PK
authors.lastname: Tam
authors.affiliation: Pathology VA Medical Center San Francisco.
authors.forename: Z Laura
authors.initials: ZL
authors.lastname: Tabatabai
authors.affiliation: Department of Medicine Institute for Human Genetics, University of California, San Francisco, USA and chris.lau@ucsf.edu.
authors.forename: Yun-Fai Chris
authors.initials: YF
authors.lastname: Lau
mesh_terms: D041322:Chromosomes, Human, Y / Q000378:metabolism; D005260:Female; D006627:Hirschsprung Disease / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D051876:Sex-Determining Region Y Protein / Q000235:genetics / Q000378:metabolism*; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human