The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors.
The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors.
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DOI：
10.1159/000512976
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发表时间：
2020
影响因子：
2.9
通讯作者：
Segal RA
中科院分区：
文献类型：
--
作者：
Merk DJ;Zhou P;Cohen SM;Pazyra-Murphy MF;Hwang GH;Rehm KJ;Alfaro J;Reid CM;Zhao X;Park E;Xu PX;Chan JA;Eck MJ;Nazemi KJ;Harwell CC;Segal RA
在神经发育过程中，干细胞和前体细胞可以对称或不对称分裂。对称性和非对称性细胞分裂之间的转变是前体细胞扩张和神经分化的主要决定因素，但调节这一转变的潜在机制尚不清楚。在这里，我们确定Sonic hedgehog(Shh)通路是调节小脑颗粒细胞前体(GCP)分裂方式的关键决定因素。利用Shh通路中的部分功能突变，我们证明了通路的激活决定了GCPs的纺锤体方向，而有丝分裂的纺锤体方向与分裂模式相关。从机制上讲，我们证明了磷酸酶Eya1对于实现Shh依赖的GCP纺锤体定向是必不可少的。我们确定非典型蛋白激酶C(APKC)是Eya1活性的直接靶标，并表明Eya1去磷酸化激活环中的关键苏氨酸(T410)。因此，Eya1使PKC失活，导致Numb和其他调节分裂模式的成分的磷酸化减少。这种依赖于Eya1的级联在连接纺锤体取向、细胞周期退出和末端分化方面是至关重要的。总之，这些发现表明，Shh-Eya1调节轴通过协调纺锤体方向和细胞命运决定因素，选择性地促进小脑发育期间的对称细胞分裂。
During neural development, stem and precursor cells can divide either symmetrically or asymmetrically. The transition between symmetric and asymmetric cell divisions is a major determinant of precursor cell expansion and neural differentiation, but the underlying mechanisms that regulate this transition are not well understood. Here, we identify the Sonic hedgehog (Shh) pathway as a critical determinant regulating the mode of division of cerebellar granule cell precursors (GCPs). Using partial gain and loss of function mutations within the Shh pathway, we show that pathway activation determines spindle orientation of GCPs, and that mitotic spindle orientation correlates with the mode of division. Mechanistically, we show that the phosphatase Eya1 is essential for implementing Shh-dependent GCP spindle orientation. We identify atypical protein kinase C (aPKC) as a direct target of Eya1 activity and show that Eya1 dephosphorylates a critical Threonine (T410) in the activation loop. Thus, Eya1 inactivates aPKC, resulting in reduced phosphorylation of Numb and other components that regulate the mode of division. This Eya1-dependent cascade is critical in linking spindle orientation, cell cycle exit and terminal differentiation. Together these findings demonstrate that a Shh-Eya1 regulatory axis selectively promotes symmetric cell divisions during cerebellar development by coordinating spindle orientation and cell fate determinants.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
11.8
作者：
Ahmed, Mohi;Wong, Elaine Y. M.;Sun, Jianbo;Xu, Jinshu;Wang, Feng;Xu, Pin-Xian
通讯作者：
Xu, Pin-Xian
影响因子：
4.6
作者：
El-Hashash, Ahmed H. K.;Turcatel, Gianluca;Warburton, David
通讯作者：
Warburton, David
影响因子：
8.8
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Auvergne RM;Sim FJ;Wang S;Chandler-Militello D;Burch J;Al Fanek Y;Davis D;Benraiss A;Walter K;Achanta P;Johnson M;Quinones-Hinojosa A;Natesan S;Ford HL;Goldman SA
通讯作者：
Goldman SA
影响因子：
11.8
作者：
Eisner A;Pazyra-Murphy MF;Durresi E;Zhou P;Zhao X;Chadwick EC;Xu PX;Hillman RT;Scott MP;Greenberg ME;Segal RA
通讯作者：
Segal RA