A Signaling Principle for the Specification of the Germ Cell Lineage in Mice
A Signaling Principle for the Specification of the Germ Cell Lineage in Mice
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DOI：
10.1016/j.cell.2009.03.014
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发表时间：
2009-05-01
期刊：
影响因子：
64.5
通讯作者：
Saitou, Mitinori
中科院分区：
文献类型：
--
作者：
Ohinata, Yasuhide;Ohta, Hiroshi;Saitou, Mitinori
生殖细胞谱系的特化对发育和遗传至关重要。在小鼠中，生殖细胞的命运是由信号分子在多能外胚层细胞中诱导的，但潜在的机制仍然未知。在这里，我们证明，生殖细胞的命运在上胚层是一个直接的后果Bmp4信号从胚外外胚层（ExE），这是拮抗前内脏内胚层（AVE）。引人注目的是，来自ExE的Bmp8b限制了AVE的发育，从而有助于Bmp4信号传导。此外，上胚层中的Wnt 3确保其对Bmp4的响应性。无血清，确定的文化表明，在响应Bmp4，主管上胚层细胞均匀表达关键的转录调节Blimp1和Prdm14和获得生殖细胞的特性，包括全基因组表观遗传重编程，在一个有序的方式。值得注意的是，诱导的细胞有助于精子发生和后代的生育力。通过识别生殖细胞特化中的信号传导原理，我们的研究建立了体外重建哺乳动物生殖细胞谱系的稳健策略。
Specification of the germ cell lineage is vital to development and heredity. In mice, the germ cell fate is induced in pluripotent epiblast cells by signaling molecules, yet the underlying mechanism remains unknown. Here we demonstrate that germ cell fate in the epiblast is a direct consequence of Bmp4 signaling from the extraembryonic ectoderm (ExE), which is antagonized by the anterior visceral endoderm (AVE). Strikingly, Bmp8b from the ExE restricts AVE development, thereby contributing to Bmp4 signaling. Furthermore, Wnt3 in the epiblast ensures its responsiveness to Bmp4. Serum-free, defined cultures revealed that, in response to Bmp4, competent epiblast cells uniformly expressed key transcriptional regulators Blimp1 and Prdm14 and acquired germ-cell properties, including genome-wide epigenetic reprogramming, in an orderly fashion. Notably, the induced cells contributed to both spermatogenesis and fertility of offspring. By identifying a signaling principle in germ cell specification, our study establishes a robust strategy for reconstituting the mammalian germ cell lineage in vitro.