Neogenin Promotes BMP2 Activation of YAP and Smad1 and Enhances Astrocytic Differentiation in Developing Mouse Neocortex
Neogenin Promotes BMP2 Activation of YAP and Smad1 and Enhances Astrocytic Differentiation in Developing Mouse Neocortex
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Neogenin 促进 BMP2 激活 YAP 和 Smad1，并增强发育中的小鼠新皮质的星形胶质细胞分化
DOI：
10.1523/jneurosci.4487-15.2016
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发表时间：
2016-05-25
影响因子：
5.3
通讯作者：
Xiong, Wen-Cheng
中科院分区：
文献类型：
--
作者：
Huang, Zhihui;Sun, Dong;Xiong, Wen-Cheng
再生素是一种DCC（deleted in colorectal cancer）家族受体，在神经干细胞（neural stem cells，NSCs）中高度表达。然而，其在神经干细胞中的功能仍有待探索。在这里，我们提供了在体外和体内的证据再生素的功能，在神经干细胞，以促进新皮层星形胶质细胞，但不是自我更新或神经分化。从机制上讲，新皮质NSC中的再生蛋白是雅普（yes相关蛋白）的BMP 2激活所必需的。活性/核雅普稳定磷酸化Smad 1/5/8，并且是BMP 2诱导星形胶质细胞分化所必需的。小鼠新皮层神经干细胞中雅普基因的缺失导致了与neogenin突变小鼠相似的新皮层星形胶质细胞发生缺陷。雅普在再生蛋白突变体NSC中的表达减少了响应于BMP 2的星形胶质细胞分化缺陷。总之，这些结果揭示了一个未被认识到的功能，再生蛋白在增加新皮层星形胶质细胞，并确定了一个途径的BMP 2-再生蛋白-YAP-Smad 1星形胶质细胞分化发育中的小鼠新皮层。星形胶质细胞是脑内主要的胶质细胞类型，在调节突触传递和信息处理以及维持中枢神经系统稳态方面起重要作用。发育过程中星形胶质细胞的异常分化导致突触可塑性功能障碍和神经心理障碍。在这里，我们提供的证据再生素的功能，在调节小鼠大脑发育过程中的新皮层星形胶质细胞的分化。我们还提供了证据的必要性再生蛋白在BMP 2/Smad 1诱导的星形胶质细胞分化通过雅普。因此，我们的研究结果确定了未被识别的功能，再生蛋白在小鼠新皮层星形胶质细胞的分化，并提出了一个信号通路，BMP 2-再生蛋白-YAP-Smad 1，潜在的星形胶质细胞在发育中的小鼠新皮层。
Neogenin, a DCC (deleted in colorectal cancer) family receptor, is highly expressed in neural stem cells (NSCs). However, its function in NSCs remains to be explored. Here we provide in vitro and in vivo evidence for neogenin's function in NSCs to promote neocortical astrogliogenesis, but not self-renewal or neural differentiation. Mechanistically, neogenin in neocortical NSCs was required for BMP2 activation of YAP (yes associated protein). The active/nuclear YAP stabilized phospho-Smad1/5/8 and was necessary for BMP2 induction of astrocytic differentiation. Deletion of yap in mouse neocortical NSCs caused a similar deficit in neocortical astrogliogenesis as that in neogenin mutant mice. Expression of YAP in neogenin mutant NSCs diminished the astrocytic differentiation deficit in response to BMP2. Together, these results reveal an unrecognized function of neogenin in increasing neocortical astrogliogenesis, and identify a pathway of BMP2-neogenin-YAP-Smad1 for astrocytic differentiation in developing mouse neocortex. SIGNIFICANCE STATEMENT Astrocytes, a major type of glial cells in the brain, play important roles in modulating synaptic transmission and information processing, and maintaining CNS homeostasis. The abnormal astrocytic differentiation during development contributes to dysfunctions of synaptic plasticity and neuropsychological disorders. Here we provide evidence for neogenin's function in regulation of the neocortical astrocyte differentiation during mouse brain development. We also provide evidence for the necessity of neogenin in BMP2/Smad1-induced astrocyte differentiation through YAP. Thus, our findings identify an unrecognized function of neogenin in mouse neocortical astrocyte differentiation, and suggest a signaling pathway, BMP2-neogenin-YAP-Smad1, underlying astrogliogenesis in developing mouse neocortex.