YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation
YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation
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YAP 稳定 SMAD1 并促进 BMP2 诱导的新皮质星形细胞分化
DOI：
10.1242/dev.130658
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发表时间：
2016-07-01
期刊：
影响因子：
4.6
通讯作者：
Xiong, Wen-Cheng
中科院分区：
文献类型：
--
作者：
Huang, Zhihui;Hu, Jinxia;Xiong, Wen-Cheng
雅普（yes相关蛋白）是一种受Hippo通路负调控的关键转录辅因子，对包括肝脏在内的多个器官的发育和大小控制至关重要。然而，它在大脑中的作用仍不清楚。在这里，我们提供了雅普调节小鼠新皮质星形胶质细胞分化和增殖的证据。雅普在神经元中检测不到，但选择性地在神经干细胞和星形胶质细胞中表达。NSC中的雅普是新皮质星形胶质细胞分化所必需的，在自我更新或神经分化中没有明显的作用。而星形胶质细胞中的雅普是星形胶质细胞增殖所必需的。雅普（Yap 1）敲除、Yapnestin条件性敲除和YapGFAP条件性敲除小鼠显示较少的新皮质星形胶质细胞和受损的星形胶质细胞增殖，并且因此显示新皮质神经元死亡。从机制上讲，雅普被BMP 2激活，并且活性/核雅普对于BMP 2诱导和SMAD 1的稳定以及星形胶质细胞分化至关重要。SMAD 1在YAP缺陷型神经干细胞中的表达部分地挽救了响应于BMP 2的星形胶质细胞分化缺陷。总之，这些结果确定了雅普在新皮质星形胶质细胞分化和增殖中的新功能，并揭示了发育中小鼠新皮质星形胶质细胞分化的BMP 2-YAP-SMAD 1通路。
YAP (yes-associated protein), a key transcriptional co-factor that is negatively regulated by the Hippo pathway, is crucial for the development and size control of multiple organs, including the liver. However, its role in the brain remains unclear. Here, we provide evidence for YAP regulation of mouse neocortical astrocytic differentiation and proliferation. YAP was undetectable in neurons, but selectively expressed in neural stem cells (NSCs) and astrocytes. YAP in NSCs was required for neocortical astrocytic differentiation, with no apparent role in self-renewal or neural differentiation. However, YAP in astrocytes was necessary for astrocytic proliferation. Yap (Yap1) knockout, Yapnestin conditional knockout and YapGFAP conditional knockout mice displayed fewer neocortical astrocytes and impaired astrocytic proliferation and, consequently, death of neocortical neurons. Mechanistically, YAP was activated by BMP2, and the active/nuclear YAP was crucial for BMP2 induction and stabilization of SMAD1 and astrocytic differentiation. Expression of SMAD1 in YAP-deficient NSCs partially rescued the astrocytic differentiation deficit in response to BMP2. Taken together, these results identify a novel function of YAP in neocortical astrocytic differentiation and proliferation, and reveal a BMP2-YAP-SMAD1 pathway underlying astrocytic differentiation in the developing mouse neocortex.