Identification of SOX3 as an XX male sex reversal gene in mice and humans
Edwina Sutton, … , Robin Lovell-Badge, Paul Thomas
Edwina Sutton, … , Robin Lovell-Badge, Paul Thomas
Published December 22, 2010
Citation Information: J Clin Invest. 2011;121(1):328-341. https://doi.org/10.1172/JCI42580.
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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

Edwina Sutton, James Hughes, Stefan White, Ryohei Sekido, Jacqueline Tan, Valerie Arboleda, Nicholas Rogers, Kevin Knower, Lynn Rowley, Helen Eyre, Karine Rizzoti, Dale McAninch, Joao Goncalves, Jennie Slee, Erin Turbitt, Damien Bruno, Henrik Bengtsson, Vincent Harley, Eric Vilain, Andrew Sinclair, Robin Lovell-Badge, Paul Thomas

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Figure 5

The Sox3 transgene is not able to mimic Sox9 in the gonad at 12.

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The Sox3 transgene is not able to mimic Sox9 in the gonad at 12. dp...
dpc. (A–F) XY Sox3-SrTg;Sox9fl/fl;R26CreERT2 mice were either treated or not treated with tamoxifen (TM). In the absence of TM, the gonad developed into a normal testis containing testis cords (A–C). When Sox9 was ablated after TM treatment, testis cords were not formed (D and E), and Foxl2-positive cells were detected in the gonad (F). (G–L) Similar experiments were performed for XX Sox3-SrTg;Sox9fl/fl;R26CreERT2 mice. The mice developed XX sex-reversed testis without TM (G–I). In contrast, TM treatment resulted in ovarian morphology and the expression of Foxl2 (J–L). Scale bars: 0.5 mm (A, D, G, and J) and 50 μm (B, C, E, F, H, I, K, and L).