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Title: Identification of SOX3 as an XX male sex reversal gene in mice and humans
Authors: Sutton, Edwina
Hughes, James
White, Stefan
Sekido, Ryohei
Tan, Jacqueline
Arboleda, Valerie
Rogers, Nicholas
Knower, Kevin
Rowley, Lynn
Eyre, Helen
Rizzoti, Karine
McAninch, Dale
Gonçalves, João
Slee, Jennie
Turbitt, Erin
Bruno, Damien
Bengtsson, Henrik
Harley, Vincent
Vilain, Eric
Sinclair, Andrew
Lovell-Badge, Robin
Thomas, Paul
Keywords: Doença Genéticas
XX Male
Homem XX
Sex Reversal
Reversão Sexual
Determinação do Sexo
Sex Determination
Issue Date: Jan-2011
Publisher: American Society for Clinical Investigation
Citation: J Clin Invest. 2011 Jan;121(1):328-41. Epub 2010 Dec 22
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.
Peer review: yes
ISSN: 0021-9738
Publisher Version:
Appears in Collections:DGH - Artigos em revistas internacionais

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