Notch promotes neural lineage entry by pluripotent embryonic stem cells.
Notch promotes neural lineage entry by pluripotent embryonic stem cells.
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DOI：
10.1371/journal.pbio.0040121
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发表时间：
2006-05
期刊：
影响因子：
9.8
通讯作者：
Smith, Austin G
中科院分区：
文献类型：
--
作者：
Lowell, Sally;Benchoua, Alexandra;Heavey, Barry;Smith, Austin G
胚胎干（ES）细胞生物学的一个核心挑战是了解如何对初级谱系定型施加方向。在基础培养条件下，大多数ES细胞异步转化为神经细胞。然而，许多细胞抵抗分化，而其他细胞则采取非神经命运。镶嵌激活的神经报告索克斯绿色荧光蛋白表明调节细胞间的相互作用。我们检测了小鼠ES细胞中Notch受体和配体的表达，并研究了该途径的作用。组成性激活Notch的遗传操作不会改变干细胞表型。然而，在撤销自我更新刺激后，分化被快速且专门地引导到神经谱系中。相反，药理学或遗传干扰Notch信号抑制神经命运的选择。Notch促进神经定型需要通过成纤维细胞生长因子受体的平行信号传导。表达Notch配体的基质细胞刺激人ES细胞的神经特化，表明这是多能干细胞中的保守途径。这些发现定义了Notch在ES细胞命运决定中的意想不到的决定性作用。限制内源性Notch的激活导致异质性谱系定型。因此，Notch信号传导的操纵可能是控制ES细胞谱系选择的关键因素。 遗传操作揭示了Notch信号在促进和指导胚胎干细胞向神经命运和抑制分化为其他谱系中的新作用。
A central challenge in embryonic stem (ES) cell biology is to understand how to impose direction on primary lineage commitment. In basal culture conditions, the majority of ES cells convert asynchronously into neural cells. However, many cells resist differentiation and others adopt nonneural fates. Mosaic activation of the neural reporter Sox-green fluorescent protein suggests regulation by cell-cell interactions. We detected expression of Notch receptors and ligands in mouse ES cells and investigated the role of this pathway. Genetic manipulation to activate Notch constitutively does not alter the stem cell phenotype. However, upon withdrawal of self-renewal stimuli, differentiation is directed rapidly and exclusively into the neural lineage. Conversely, pharmacological or genetic interference with Notch signalling suppresses the neural fate choice. Notch promotion of neural commitment requires parallel signalling through the fibroblast growth factor receptor. Stromal cells expressing Notch ligand stimulate neural specification of human ES cells, indicating that this is a conserved pathway in pluripotent stem cells. These findings define an unexpected and decisive role for Notch in ES cell fate determination. Limiting activation of endogenous Notch results in heterogeneous lineage commitment. Manipulation of Notch signalling is therefore likely to be a key factor in taking command of ES cell lineage choice. Genetic manipulations reveal a novel role of Notch signaling in promoting and directing embryonic stem cells toward neural fates and suppressing differentiation into other lineages.