Primordial Dwarfism Gene Maintains Lin28 Expression to Safeguard Embryonic Stem Cells from Premature Differentiation
Primordial Dwarfism Gene Maintains Lin28 Expression to Safeguard Embryonic Stem Cells from Premature Differentiation
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原始侏儒症基因维持 Lin28 表达，以保护胚胎干细胞免于过早分化。
DOI：
10.1016/j.celrep.2014.03.053
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发表时间：
2014-05-01
期刊：
影响因子：
8.8
通讯作者：
Li, Qintong
中科院分区：
文献类型：
--
作者：
Dai, Qian;Luan, Guangxin;Li, Qintong
原始侏儒症（PD）的特点是在胚胎发生和出生后的整体生长失败。La核糖核蛋白结构域家族成员7 （LAPR7）的生殖系功能缺失突变最近被发现与PD有关。矛盾的是，LARP7缺陷以前被认为通过激活正转录延伸因子b （P-TEFb）与细胞生长和增殖增加有关。在这里，我们发现Larp7缺陷可能不会显著增加P-TEFb活性。我们进一步发现，Larp7敲低并不影响胚胎干细胞的多能性，而是通过下调机体生长的正调节因子Lin28来启动胚胎干细胞（ESCs）的分化。在机制上，我们发现Larp7与聚(a)聚合酶Star-PAP相互作用以维持Lin28 mRNA的稳定性。我们认为，正确调控Lin28和PTEFb对于胚胎细胞在分化前实现足够数量的细胞分裂并最终保持适当的组织大小至关重要。
Primordial dwarfism (PD) is characterized by global growth failure, both during embryogenesis and postnatally. Loss-of-function germline mutations in La ribonucleoprotein domain family, member 7 (LAPR7) have recently been linked to PD. Paradoxically, LARP7 deficiency was previously assumed to be associated with increased cell growth and proliferation via activation of positive transcription elongation factor b (P-TEFb). Here, we show that Larp7 deficiency likely does not significantly increase P-TEFb activity. We further discover that Larp7 knockdown does not affect pluripotency but instead primes embryonic stem cells (ESCs) for differentiation via downregulation of Lin28, a positive regulator of organismal growth. Mechanistically, we show that Larp7 interacts with a poly(A) polymerase Star-PAP to maintain Lin28 mRNA stability. We propose that proper regulation of Lin28 and PTEFb is essential for embryonic cells to achieve a sufficient number of cell divisions prior to differentiation and ultimately to maintain proper organismal size.