Homeoproteins Six1 and Six4 Regulate Male Sex Determination and Mouse Gonadal Development
Homeoproteins Six1 and Six4 Regulate Male Sex Determination and Mouse Gonadal Development
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DOI：
10.1016/j.devcel.2013.06.018
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发表时间：
2013-08-26
影响因子：
11.8
通讯作者：
Nishinakamura, Ryuichi
中科院分区：
文献类型：
--
作者：
Fujimoto, Yuka;Tanaka, Satomi S.;Nishinakamura, Ryuichi
Y连锁基因Sty调节双能胚胎性腺中哺乳动物的性别决定。在这里，我们报告转录因子 Six1 和 Six4 是男性性腺分化所必需的。 Six1 和 Six4 一起缺失（但单独缺失）会导致 XY 突变性腺中出现男性到女性的性别逆转表型，并伴有麦粒肿激活失败。在突变胚胎中还发现，Sly 表达开始时性腺前体细胞形成减少，并且两性性腺尺寸减小。 XY突变体性腺中的强制麦粒肿转基因表达挽救了睾丸发育，但并未对前体生长造成最初的破坏。此外，我们还确定了 Six1/Six4 在性腺发育中的两个下游靶标，Fog2 (Zfpm2) 和 Nr5a1 (Ad4BP/Sf1)。这两种不同的 Six1/Six4 调控途径被认为对性腺发育至关重要。 Fog2 的调节在男性性别决定中诱导 Sty 表达，Nr5a1 在性腺前体形成中的调节决定性腺大小。
The Y-linked gene Sty regulates mammalian sex determination in bipotential embryonic gonads. Here, we report that the transcription factors Six1 and Six4 are required for male gonadal differentiation. Loss of Six1 and Six4 together, but neither alone, resulted in a male-to-female sex-reversal phenotype in XY mutant gonads accompanied by a failure in Sty activation. Decreased gonadal precursor cell formation at the onset of Sly expression and a gonadal size reduction in both sexes were also found in mutant embryos. Forced Sty transgene expression in XY mutant gonads rescued testicular development but not the initial disruption to precursor growth. Furthermore, we identified two downstream targets of Six1/Six4 in gonadal development, Fog2 (Zfpm2) and Nr5a1 (Ad4BP/Sf1). These two distinct Six1/Six4-regulated pathways are considered to be crucial for gonadal development. The regulation of Fog2 induces Sty expression in male sex determination, and the regulation of Nr5a1 in gonadal precursor formation determines gonadal size.