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.
Dev Neurosci

中文翻译：

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Eya1 磷酸酶介导 Shh 驱动的小脑颗粒细胞前体的对称细胞分裂

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。对称和不对称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，但调节这种转变的潜在机制尚不清楚。在这里，我们将 Sonic hedgehog (Shh) 通路确定为调节小脑颗粒细胞前体细胞 (GCP) 分裂模式的关键决定因素。使用 Shh 通路内的部分功能获得和功能突变损失，我们表明通路激活决定了 GCP 的纺锤体方向，并且有丝分裂纺锤体方向与分裂模式相关。从机制上讲，我们表明磷酸酶 Eya1 对于实现依赖于 Shh 的 GCP 纺锤体方向至关重要。我们将非典型蛋白激酶 C (aPKC) 鉴定为 Eya1 活性的直接靶标，并表明 Eya1 使激活环中的关键苏氨酸 (T410) 去磷酸化。因此，Eya1 使 aPKC 失活，导致 Numb 和调节分裂模式的其他成分的磷酸化减少。这种依赖于 Eya1 的级联对于连接纺锤体方向、细胞周期退出和终末分化至关重要。这些发现共同表明，Shh-Eya1 调节轴通过协调纺锤体方向和细胞命运决定因素，在小脑发育过程中选择性地促进对称细胞分裂。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 的级联对于连接纺锤体方向、细胞周期退出和终末分化至关重要。这些发现共同表明，Shh-Eya1 调节轴通过协调纺锤体方向和细胞命运决定因素，在小脑发育过程中选择性地促进对称细胞分裂。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 的级联对于连接纺锤体方向、细胞周期退出和终末分化至关重要。这些发现共同表明，Shh-Eya1 调节轴通过协调纺锤体方向和细胞命运决定因素，在小脑发育过程中选择性地促进对称细胞分裂。
开发神经科学