title: Conserved regulatory modules in the Sox9 testis-specific enhancer predict roles for SOX, TCF/LEF, Forkhead, DMRT, and GATA proteins in vertebrate sex determination.
abstract: While the primary sex determining switch varies between vertebrate species, a key downstream event in testicular development, namely the male-specific up-regulation of Sox9, is conserved. To date, only two sex determining switch genes have been identified, Sry in mammals and the Dmrt1-related gene Dmy (Dmrt1bY) in the medaka fish Oryzias latipes. In mice, Sox9 expression is evidently up-regulated by SRY and maintained by SOX9 both of which directly activate the core 1.3 kb testis-specific enhancer of Sox9 (TESCO). How Sox9 expression is up-regulated and maintained in species without Sry (i.e. non-mammalian species) is not understood. In this study, we have undertaken an in-depth comparative genomics approach and show that TESCO contains an evolutionarily conserved region (ECR) of 180 bp which is present in marsupials, monotremes, birds, reptiles and amphibians. The ECR contains highly conserved modules that predict regulatory roles for SOX, TCF/LEF, Forkhead, DMRT, and GATA proteins in vertebrate sex determination/differentiation. Our data suggest that tetrapods share common aspects of Sox9 regulation in the testis, despite having different sex determining switch mechanisms. They also suggest that Sox9 autoregulation is an ancient mechanism shared by all tetrapods, raising the possibility that in mammals, SRY evolved by mimicking this regulation. The validation of ECR regulatory sequences conserved from human to frogs will provide new insights into vertebrate sex determination.
authors.affiliation: Prince Henry's Institute for Medical Research, PO Box 5152, Clayton, VIC 3168, Australia.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bagheri-Fam
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sinclair
authors.forename: Peter
authors.initials: P
authors.lastname: Koopman
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Harley
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D019143:Evolution, Molecular; D016678:Genome / Q000235:genetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000235:genetics; D010802:Phylogeny; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D019849:Sex Determination Processes; D013737:Testis / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014714:Vertebrates / Q000235:genetics*
chemical_list: D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D014157:Transcription Factors