title: The male-determining gene SRY is a hybrid of DGCR8 and SOX3, and is regulated by the transcription factor CP2.
abstract: In mammals, sex is determined by the presence or absence of the Y chromosome that bears a male-dominant sex-determining gene SRY, which switches the differentiation of gonads into male testes. The molecular signaling mechanism turning on the switch, however, has remained unclear for 18 years since the identification of the gene. Here, we describe how this gene emerged and started to work. From amino acid homology, we realized that SRY is a hybrid gene between a portion of the first exon of DiGeorge syndrome critical region gene 8 (DGCR8) and the high-mobility group (HMG) box of SRY box-3 (SOX3) gene. We identified the regulatory sequence in the SRY promotor region by searching for a common motif shared with DGCR8 mRNA. From the motif search between DGCR8 mRNA and the SRY upstream sequence, we found that the transcription factor CP2 (TFCP2) binding motif is present in both. TFCP2 overexpression did not show a significant increase of SRY mRNA expression, and TFCP2 suppression by RNA interference (RNAi) significantly reduced SRY mRNA expression. Furthermore, electrophoretic mobility shift assay (EMSA) demonstrated that TFCP2 acts as a regulator by directly binding to the SRY promoter. We conclude that SRY is a hybrid gene composed of two genes, DGCR8 and SOX3; and TFCP2 is an essential transcription factor for SRY expression regulation.
authors.affiliation: Department of Human Genetics and Public Health, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. sato@basic.med.tokushima-u.ac.jp
authors.forename: Youichi
authors.initials: Y
authors.lastname: Sato
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Shinka
authors.forename: Kozue
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Ashraf A
authors.initials: AA
authors.lastname: Ewis
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakahori
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D050506:Mutant Chimeric Proteins / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D016601:RNA-Binding Proteins; D020218:Response Elements / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000502:physiology; D017385:Sequence Homology; D019849:Sex Determination Processes; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014162:Transfection
chemical_list: C474043:DGCR8 protein, human; D004268:DNA-Binding Proteins; D050506:Mutant Chimeric Proteins; D011506:Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C490906:SOX1 protein, human; C527785:SOX3 protein, human; D055748:SOXB1 Transcription Factors; C501906:TFCP2 protein, human; D014157:Transcription Factors