Sexual Fate Change of XX Germ Cells Caused by the Deletion of SMAD4 and STRA8 Independent of Somatic Sex Reprogramming.
Sexual Fate Change of XX Germ Cells Caused by the Deletion of SMAD4 and STRA8 Independent of Somatic Sex Reprogramming.
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DOI：
10.1371/journal.pbio.1002553
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发表时间：
2016-09
期刊：
影响因子：
9.8
通讯作者：
Saga Y
中科院分区：
文献类型：
--
作者：
Wu Q;Fukuda K;Kato Y;Zhou Z;Deng CX;Saga Y
性腺中精子和卵子的差异编程是生殖生物学的一个基本问题。尽管生殖细胞的性命运被认为是由来自胎儿性腺性别分化体细胞的信号因子决定的，但决定生殖细胞命运的分子机制尚不清楚。在这里，我们发现生殖细胞中抗十肢截瘫同源物4 （SMAD4）的母体是雌性型分化所必需的。SMAD4缺失卵巢中的生殖细胞响应维甲酸信号，但不能经历减数分裂前期I，这与卵泡形成所需基因的较弱表达相吻合，表明SMAD4信号对于卵母细胞分化和减数分裂进程至关重要。有趣的是，在没有stra8的雌性生殖细胞中，Smad4的种系特异性缺失导致雄性性腺细胞分化所需的基因上调，包括Nanos2和PLZF，这表明卵巢中开始了雄性型分化。此外，我们对突变卵巢的转录组分析表明，在体细胞中没有全局基因表达变化的情况下实现了性别改变表型。我们的研究结果表明SMAD4和STRA8是调节生殖细胞雌性命运的重要因子。SMAD4和STRA8的双重消融导致XX生殖细胞由雌向雄转换，而不影响体细胞命运。这表明SMAD4和STRA8是决定生殖细胞雌性命运的重要内在因素，共同抑制雄性基因的表达。哺乳动物的性别取决于男性特有的基因，性别决定区Y (SRY)，它位于Y染色体上。缺乏这种基因的个体将发育为雌性。因此，在没有SRY的情况下，生殖细胞的命运也会从男性改变到女性。因此，认为体细胞调节生殖细胞成为精子或卵母细胞。然而，什么因素决定生殖细胞的性别命运在很大程度上是未知的。在胎儿卵巢中，维甲酸（RA）启动生殖细胞中STRA8的表达并诱导减数分裂。没有STRA8的雌性生殖细胞不能进入减数分裂，但仍能进入卵发生并形成卵母细胞样细胞，表明RA不是卵发生的调节剂。在这里，我们发现缺乏SMAD4和STRA8（但不是单一敲除）的雌性生殖细胞在卵巢中发育为雄性淋细胞样细胞，表明这两个因素是雌性生殖细胞的决定因素。令我们惊讶的是，在双敲除卵巢中观察到的性别命运转换并没有伴随着体细胞基因表达的变化，这揭示了一个意想不到的发现，SRY控制的体细胞因子对于生殖细胞中男性特异性基因的上调是不可或缺的。
The differential programming of sperm and eggs in gonads is a fundamental topic in reproductive biology. Although the sexual fate of germ cells is believed to be determined by signaling factors from sexually differentiated somatic cells in fetal gonads, the molecular mechanism that determines germ cell fate is poorly understood. Herein, we show that mothers against decapentaplegic homolog 4 (SMAD4) in germ cells is required for female-type differentiation. Germ cells in Smad4-deficient ovaries respond to retinoic acid signaling but fail to undergo meiotic prophase I, which coincides with the weaker expression of genes required for follicular formation, indicating that SMAD4 signaling is essential for oocyte differentiation and meiotic progression. Intriguingly, germline-specific deletion of Smad4 in Stra8-null female germ cells resulted in the up-regulation of genes required for male gonocyte differentiation, including Nanos2 and PLZF, suggesting the initiation of male-type differentiation in ovaries. Moreover, our transcriptome analyses of mutant ovaries revealed that the sex change phenotype is achieved without global gene expression changes in somatic cells. Our results demonstrate that SMAD4 and STRA8 are essential factors that regulate the female fate of germ cells. Double ablation of SMAD4 and STRA8 causes female-to-male switching of XX germ cells without affecting somatic cell fate. This suggests that SMAD4 and STRA8 are essential intrinsic factors that determine the female fate of germ cells, collaborating to suppress expression of male genes. Mammalian sex depends on a male-specific gene, sex-determining region Y (SRY), which is located on the Y chromosome. Individuals lacking this gene will develop as female. Accordingly, germ cell fate also changes from male to female in the absence of SRY. Therefore, it is thought that somatic cells regulate germ cells to become sperm or oocytes. However, it is largely unknown what factor is responsible for sexual fate determination in germ cells. In fetal ovaries, retinoic acid (RA) initiates STRA8 expression in germ cells and induces meiosis. Female germ cells without STRA8 fail to enter meiosis but still progress to oogenesis and form oocyte-like cells, indicating that RA is not the regulator of oogenesis. Here, we found that female germ cells lacking both SMAD4 and STRA8 (but not a single knockout) develop as male gonocyte-like cells in ovaries, indicating that these two factors work as female germ cell determinants. To our surprise, the sexual fate switch observed in the double knockout ovary is not accompanied by gene expression changes in somatic cells, revealing the unexpected finding that somatic factors controlled by SRY are dispensable for the upregulation of male-specific genes in germ cells.
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