A Mesodermal Factor, T, Specifies Mouse Germ Cell Fate by Directly Activating Germline Determinants
A Mesodermal Factor, T, Specifies Mouse Germ Cell Fate by Directly Activating Germline Determinants
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DOI：
10.1016/j.devcel.2013.11.001
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发表时间：
2013-12-09
影响因子：
11.8
通讯作者：
Saitou, Mitinori
中科院分区：
文献类型：
--
作者：
Aramaki, Shinya;Hayashi, Katsuhiko;Saitou, Mitinori
生殖细胞确保繁殖和遗传。在小鼠中，BMP4 和 WNT3 在多能外胚层中诱导原始生殖细胞 (PGC)（精子和卵母细胞的前体），但其潜在机制仍不清楚。在这里，使用体外 PGC 规范系统，我们表明 WNT3 通过 β-CATENIN 诱导外胚层样细胞中许多与中胚层相关的转录因子。其中，T (BRACHYURY) 是一种经典且保守的中胚层因子，对于两个种系决定因子 Blimp1 和 Prdm14 的强力激活至关重要。 T（但不是 SMAD1 或 TCF1）结合 Blimp1 和 Prdm14 的不同调控元件，并直接上调这些基因，描绘下游 PGC 程序。如果没有 BMP4，WNT3 诱导的程序会阻止 T 激活 Blimp1 和 Prdm14，这证明了 BMP4 在 PGC 规范中的许可作用。这些发现确立了哺乳动物 PGC 规范中中胚层因子的关键信号传导机制和基本作用。
Germ cells ensure reproduction and heredity. In mice, primordial germ cells (PGCs), the precursors for spermatozoa and oocytes, are induced in pluripotent epiblast by BMP4 and WNT3, yet the underlying mechanism remains unclear. Here, using an in vitro PGC specification system, we show that WNT3 induces many transcription factors associated with mesoderm in epiblast-like cells through beta-CATENIN. Among these, T (BRACHYURY), a classical and conserved mesodermal factor, was essential for robust activation of Blimp1 and Prdm14, two of the germline determinants. T, but not SMAD1 or TCF1, binds distinct regulatory elements of both Blimp1 and Prdm14 and directly upregulates these genes, delineating the downstream PGC program. Without BMP4, a program induced by WNT3 prevents T from activating Blimp1 and Prdm14, demonstrating a permissive role of BMP4 in PGC specification. These findings establish the key signaling mechanism for, and a fundamental role of a mesodermal factor in, mammalian PGC specification.