DMRT1 prevents female reprogramming in the postnatal mammalian testis.
DMRT1 prevents female reprogramming in the postnatal mammalian testis.
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DOI：
10.1038/nature10239
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发表时间：
2011-07-20
期刊：
影响因子：
64.8
通讯作者：
Zarkower, David
中科院分区：
文献类型：
--
作者：
Matson, Clinton K.;Murphy, Mark W.;Sarver, Aaron L.;Griswold, Michael D.;Bardwell, Vivian J.;Zarkower, David
哺乳动物的性别在胎儿性腺中由Y染色体基因Sry的存在或不存在决定，该基因控制双能前体细胞分化为睾丸支持细胞或卵巢颗粒细胞。这种在单一性腺细胞类型中的关键决定最终控制整个身体的性分化。性别决定可以被视为男性调节基因网络（其中Sry激活Sox 9）和女性网络（涉及Wnt/β-连环蛋白信号传导）之间争夺胎儿性腺中的首要地位的斗争（补充图1）。在女性中，主要的性别决定不是最终的：在成年颗粒细胞中FOXL 2转录因子的丢失可以将颗粒细胞重新编程为支持细胞。在这里，我们表明，性的命运也是令人惊讶的不稳定的睾丸：在小鼠支持细胞中的DMRT 1转录因子的损失，即使在成年人中，激活Foxl 2和重新编程支持细胞成颗粒细胞。在这种环境中，卵泡膜细胞形成，雌激素产生，生殖细胞出现女性化。因此，Dmrt 1是必不可少的，以维持哺乳动物的睾丸决定，和竞争的调节网络保持性腺性别后，很长一段时间的胎儿选择男性和女性。Dmrt 1和Foxl 2在整个脊椎动物中是保守的，Dmrt 1相关的性调节因子在整个后生动物中也是保守的。因此，Dmrt 1和Foxl 2之间控制性腺性别的拮抗作用可能超出哺乳动物。由于Dmrt 1丢失而导致的重编程也可能有助于解释与DMRT 1相关的人类综合征的病因，包括性分化障碍和睾丸癌。
Sex in mammals is determined in the foetal gonad by the presence or absence of the Y chromosome gene Sry, which controls whether bipotential precursor cells differentiate into testicular Sertoli cells or ovarian granulosa cells. This pivotal decision in a single gonadal cell type ultimately controls sexual differentiation throughout the body. Sex determination can be viewed as a battle for primacy in the foetal gonad between a male regulatory gene network in which Sry activates Sox9 and a female network involving Wnt/β-catenin signaling (Supplemental Fig. 1). In females the primary sex-determining decision is not final: loss of the FOXL2 transcription factor in adult granulosa cells can reprogramme granulosa cells into Sertoli cells. Here we show that sexual fate is also surprisingly labile in the testis: loss of the DMRT1 transcription factor in mouse Sertoli cells, even in adults, activates Foxl2 and reprogrammes Sertoli cells into granulosa cells. In this environment, theca cells form, oestrogen is produced, and germ cells appear feminized. Thus Dmrt1 is essential to maintain mammalian testis determination, and competing regulatory networks maintain gonadal sex long after the foetal choice between male and female. Dmrt1 and Foxl2 are conserved throughout vertebrates and Dmrt1-related sexual regulators are conserved throughout metazoans. Antagonism between Dmrt1 and Foxl2 for control of gonadal sex may therefore extend beyond mammals. Reprogramming due to loss of Dmrt1 also may help explain the etiology of human syndromes linked to DMRT1, including disorders of sexual differentiation and testicular cancer.
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