Distinct functions of BMP4 during different stages of mouse ES cell neural commitment
Distinct functions of BMP4 during different stages of mouse ES cell neural commitment
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BMP4在小鼠ES细胞神经定型不同阶段的独特功能
DOI：
10.1242/dev.049494
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发表时间：
2010-07-01
期刊：
影响因子：
4.6
通讯作者：
Jing, Naihe
中科院分区：
文献类型：
--
作者：
Zhang, Kejing;Li, Lingyu;Jing, Naihe
骨形态发生蛋白（BMP）信号在维持小鼠胚胎干细胞（ESCs）多能性方面起着至关重要的作用，但对ESC的神经分化有负面影响。然而，目前尚不清楚BMP信号在神经承诺过程中何时以及如何执行这些不同的功能。在这里，我们表明，BMP 4敏感的窗口存在于ESC神经分化。在这个特定时期的细胞对应于卵柱期上胚层，并且可以维持为ESC衍生的上胚层干细胞（ESD-EpiSC），其具有与源自小鼠胚胎的EpiSC相同的特征。我们提出ESC神经分化发生在两个阶段：首先从ESC到ESD-EpiSC，然后从ESD-EpiSC到神经前体细胞（NPC）。我们进一步表明，BMP 4在第一阶段抑制ESC向ESD-EpiSC的转化，并在第二阶段抑制ESD-EpiSC神经定型并促进非神经谱系分化。机制研究表明，BMP 4在第一阶段抑制FGF/ERK活性，而在第二阶段不抑制; ID作为BMP信号传导的重要下游基因，在两个阶段都部分替代了BMP 4的功能。我们的结论是，BMP信号在ESC神经定型的不同阶段有不同的功能。
Bone morphogenetic protein (BMP) signaling plays a crucial role in maintaining the pluripotency of mouse embryonic stem cells (ESCs) and has negative effects on ESC neural differentiation. However, it remains unclear when and how BMP signaling executes those different functions during neural commitment. Here, we show that a BMP4-sensitive window exists during ESC neural differentiation. Cells at this specific period correspond to the egg cylinder stage epiblast and can be maintained as ESC-derived epiblast stem cells (ESD-EpiSCs), which have the same characteristics as EpiSCs derived from mouse embryos. We propose that ESC neural differentiation occurs in two stages: first from ESCs to ESD-EpiSCs and then from ESD-EpiSCs to neural precursor cells (NPCs). We further show that BMP4 inhibits the conversion of ESCs into ESD-EpiSCs during the first stage, and suppresses ESD-EpiSC neural commitment and promotes non-neural lineage differentiation during the second stage. Mechanistic studies show that BMP4 inhibits FGF/ERK activity at the first stage but not at the second stage; and IDs, as important downstream genes of BMP signaling, partially substitute for BMP4 functions at both stages. We conclude that BMP signaling has distinct functions during different stages of ESC neural commitment.