DAZL limits pluripotency, differentiation, and apoptosis in developing primordial germ cells.
DAZL limits pluripotency, differentiation, and apoptosis in developing primordial germ cells.
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DOI：
10.1016/j.stemcr.2014.09.003
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发表时间：
2014-11-11
影响因子：
5.9
通讯作者：
Geijsen, Niels
中科院分区：
文献类型：
--
作者：
Chen, Hsu-Hsin;Welling, Maaike;Bloch, Donald B.;Munoz, Javier;Mientjes, Edwin;Chen, Xinjie;Tramp, Cody;Wu, Jie;Yabuuchi, Akiko;Chou, Yu-Fen;Buecker, Christa;Krainer, Adrian;Willemsen, Rob;Heck, Albert J.;Geijsen, Niels
发育中的哺乳动物胚胎中原始生殖细胞（PGC）的缺乏阻碍了对早期生殖细胞形成过程的强有力的生化分析。在这里，我们证明 DAZL（一种生殖细胞特异性 RNA 结合蛋白）是体外生殖细胞发育过程中强大的 PGC 标记物。使用 Dazl-GFP 报告基因 ESC，我们证明 DAZL 在大型 mRNA/蛋白质相互作用网络中发挥核心作用，该网络阻止核心多能因子（包括 Sox2 和 Sall4）以及 Suz12（多能细胞分化所需的多梳家族成员）的翻译。因此，DAZL 限制新生 PGC 的多能性和体细胞分化。此外，我们观察到 DAZL 与关键 Caspases 的 mRNA 相关，并类似地抑制其翻译。这种优雅的自动防故障机制确保，虽然 DAZL 的缺失会导致多能因子的延长表达，但由于细胞凋亡级联的伴随激活，可以避免畸胎瘤的形成。 DAZL 与颗粒结构中的翻译抑制剂网络共定位 DAZL 与关键多能性基因和 Caspases 的 mRNA 转录物相互作用 DAZL 功能的丧失会导致多能性基因的延长表达 DAZL 的丧失会导致 Caspases 的表达，从而导致 PGC 凋亡 在本文中，Geijsen 及其同事证明 DAZL 在发育中的原始胚中充当多能性、分化和凋亡的翻译抑制因子细胞。因此，DAZL 限制多能性，同时防止体细胞分化，并为 PGC 系统提供了一种优雅的故障安全机制，其中多能性调节的丧失同时触发生殖细胞死亡并防止生殖细胞肿瘤形成。
The scarcity of primordial germ cells (PGCs) in the developing mammalian embryo hampers robust biochemical analysis of the processes that underlie early germ cell formation. Here, we demonstrate that DAZL, a germ cell-specific RNA binding protein, is a robust PGC marker during in vitro germ cell development. Using Dazl-GFP reporter ESCs, we demonstrate that DAZL plays a central role in a large mRNA/protein interactive network that blocks the translation of core pluripotency factors, including Sox2 and Sall4, as well as of Suz12, a polycomb family member required for differentiation of pluripotent cells. Thus, DAZL limits both pluripotency and somatic differentiation in nascent PGCs. In addition, we observed that DAZL associates with mRNAs of key Caspases and similarly inhibits their translation. This elegant fail-safe mechanism ensures that, whereas loss of DAZL results in prolonged expression of pluripotency factors, teratoma formation is avoided due to the concomitant activation of the apoptotic cascade. DAZL colocalizes with a network of translational inhibitors in granular structures DAZL interacts with mRNA transcripts of key pluripotency genes and Caspases Loss of DAZL function leads to prolonged expression of pluripotency genes Loss of DAZL leads to expression of Caspases, resulting in apoptosis in PGCs In this article, Geijsen and colleagues demonstrate that DAZL acts as a translational suppressor of pluripotency, differentiation, and apoptosis in developing primordial germ cells. As such, DAZL limits pluripotency while simultaneously preventing somatic differentiation and provides an elegant fail-safe mechanism into the PGC system, in which the loss of pluripotency regulation simultaneously triggers germ cell death and prevents germ cell tumor formation.
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