Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Hum Mol Genet. 2010 Feb 1;19(3):506-16. doi: 10.1093/hmg/ddp520. Epub 2009 Nov 20.
Male development in mammals is normally initiated by the Y-linked gene Sry, which activates expression of Sox9, leading to a cascade of gene activity required for testis formation. Although defects in this genetic cascade lead to human disorders of sex development (DSD), only a dozen DSD genes have been identified, and causes of 46,XX DSD (XX maleness) other than SRY translocation are almost completely unknown. Here, we show that transgenic expression of Sox10, a close relative of Sox9, in gonads of XX mice resulted in development of testes and male physiology. The degree of sex reversal correlated with levels of Sox10 expression in different transgenic lines. Sox10 was expressed at low levels in primordial gonads of both sexes during normal mouse development, becoming male-specific during testis differentiation. SOX10 protein was able to activate transcriptional targets of SOX9, explaining at a mechanistic level its ability to direct male development. Because over-expression of SOX10 alone is able to mimic the XX DSD phenotypes associated with duplication of human chromosome 22q13, and given that human SOX10 maps to 22q13.1, our results functionally implicate SOX10 in the etiology of these DSDs.
哺乳动物的雄性发育通常由 Y 连锁基因 Sry 启动，该基因激活 Sox9 的表达，导致一系列基因活性，这些基因活性是睾丸形成所必需的。尽管这种遗传级联的缺陷会导致人类性别发育障碍（DSD），但仅鉴定出十几个 DSD 基因，并且除了 SRY 易位之外，导致 46,XX DSD（XX 男性）的原因几乎完全未知。在这里，我们表明 Sox10（Sox9 的近亲）在 XX 小鼠的性腺中的转基因表达导致睾丸和雄性生理的发育。性反转的程度与不同转基因系中 Sox10 的表达水平相关。在正常的小鼠发育过程中，Sox10 在两性的原始性腺中低水平表达，在睾丸分化过程中变为雄性特异性。SOX10 蛋白能够激活 SOX9 的转录靶标，从机制水平解释其指导男性发育的能力。由于单独过表达 SOX10 就能够模拟与人类染色体 22q13 重复相关的 XX DSD 表型，并且鉴于人类 SOX10 映射到 22q13.1，我们的结果在功能上暗示 SOX10 参与了这些 DSD 的病因。
