Identification of SOX3 as an XX male sex reversal gene in mice and humans
Identification of SOX3 as an XX male sex reversal gene in mice and humans
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DOI：
10.1172/jci42580
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发表时间：
2011-01-01
影响因子：
15.9
通讯作者：
Thomas, Paul
中科院分区：
文献类型：
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作者：
Sutton, Edwina;Hughes, James;Thomas, Paul
哺乳动物的性别是由基因决定的，并在细胞水平上由性染色体互补决定（XY雄性和X，C雌性）Y染色体连锁基因性别决定区Y（SRY）被认为是几乎所有真兽目和后兽目哺乳动物中雄性性别决定的主要启动子，起上调其直接靶基因Sty相关的含HMG盒基因9（SOX 9）表达的作用数据表明SRY从SOX 3进化而来，尽管没有直接的功能证据支持这一假设。实际上，SOX 3的功能丧失突变不影响小鼠或人的性别决定。为了进一步研究SOX 3的体内功能，我们产生了过表达SOX 3的转基因小鼠。在此，我们报道了在这些转基因品系之一中，Sox 3在双能性腺中异位表达，这导致频繁的完全XX雄性性别逆转进一步分析表明，Sox 3通过与Sry类似的机制上调Sox 9的表达来诱导该特定系小鼠的睾丸分化重要的是，我们还在三名XX男性性反转患者中鉴定了SOX 3调节区内的基因重排。这些数据表明，SOX3和SRY在性别决定中是功能上可互换的，并支持SRY是通过调控SRY基因表达而从SOX3进化而来的观点。导致其在早期性腺中重新表达的突变
Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and X,C 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 Sty-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 m 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 m 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