title: Identification of SOX3 as an XX male sex reversal gene in mice and humans.
abstract: Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box-containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.
authors.affiliation: School of Molecular and Biomedical Science and Australian Research Council Special Research Centre for the Molecular Genetics of Development, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Edwina
authors.initials: E
authors.lastname: Sutton
authors.forename: James
authors.initials: J
authors.lastname: Hughes
authors.forename: Stefan
authors.initials: S
authors.lastname: White
authors.forename: Ryohei
authors.initials: R
authors.lastname: Sekido
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Tan
authors.forename: Valerie
authors.initials: V
authors.lastname: Arboleda
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rogers
authors.forename: Kevin
authors.initials: K
authors.lastname: Knower
authors.forename: Lynn
authors.initials: L
authors.lastname: Rowley
authors.forename: Helen
authors.initials: H
authors.lastname: Eyre
authors.forename: Karine
authors.initials: K
authors.lastname: Rizzoti
authors.forename: Dale
authors.initials: D
authors.lastname: McAninch
authors.forename: Joao
authors.initials: J
authors.lastname: Goncalves
authors.forename: Jennie
authors.initials: J
authors.lastname: Slee
authors.forename: Erin
authors.initials: E
authors.lastname: Turbitt
authors.forename: Damien
authors.initials: D
authors.lastname: Bruno
authors.forename: Henrik
authors.initials: H
authors.lastname: Bengtsson
authors.forename: Vincent
authors.initials: V
authors.lastname: Harley
authors.forename: Eric
authors.initials: E
authors.lastname: Vilain
authors.forename: Andrew
authors.initials: A
authors.lastname: Sinclair
authors.forename: Robin
authors.initials: R
authors.lastname: Lovell-Badge
authors.forename: Paul
authors.initials: P
authors.lastname: Thomas
mesh_terms: D058531:46, XX Testicular Disorders of Sex Development / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015321:Gene Rearrangement; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D011247:Pregnancy; D012045:Regulatory Sequences, Nucleic Acid; D050697:Retinal Dehydrogenase; D055758:SOX9 Transcription Factor / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D012708:Sertoli Cells / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000196:embryology / Q000473:pathology; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; C527785:SOX3 protein, human; D055758:SOX9 Transcription Factor; D055748:SOXB1 Transcription Factors; C527786:Sox3 protein, mouse; C527933:Sox9 protein, mouse; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase