PDK1 Regulates the Lengthening of G1 Phase to Balance RGC Proliferation and Differentiation during Cortical Neurogenesis
PDK1 Regulates the Lengthening of G1 Phase to Balance RGC Proliferation and Differentiation during Cortical Neurogenesis
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PDK1 调节 G1 期的延长以平衡皮质神经发生过程中 RGC 的增殖和分化
DOI：
10.1093/cercor/bhab428
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Chunjie Zhao
中科院分区：
文献类型：
--
作者：
Xiaoning Han;Yongjie Wei;Ru Ba;Lijuan Sun;Chunjie Zhao
摘要。在皮层发育过程中，祖细胞自我更新和神经发生之间的平衡对于决定皮层的大小和形态至关重要。发育中的皮质的一个基本特征是在神经发生过程中RGCs中G1期长度的增加，这是祖细胞命运选择的关键决定因素。G1的长度是如何暂时调控的尚不清楚。在这里，AGC激酶家族的成员Pdk1被Emx1-Cre小鼠系与Pdk1fl/fl系交叉有条件地破坏。Pdk1的缺失导致细胞周期缩短，并伴有RGC增殖增加，特别是在晚期而不是早期/中期神经发生阶段，这是由于G1期延长受损。巧合的是，Pdk1 cKO皮层的核向基底的相互动力学迁移加速。因此，我们检测到P0的神经元输出增加。我们进一步发现，与对照动物相比，cKO皮层中细胞周期调节因子cyclin D1及其激活因子Myc显著上调。总之，我们已经确定了PDK1在皮层神经发生中的新作用。PDK1作为Myc-cyclin D1通路的上游调控因子，控制G1期的延长和RGC增殖与分化的平衡。
Abstract. During cortical development, the balance between progenitor self-renewal and neurogenesis is critical for determining the size/morphology of the cortex. A fundamental feature of the developing cortex is an increase in the length of G1 phase in RGCs over the course of neurogenesis, which is a key determinant of progenitor fate choice. How the G1 length is temporally regulated remains unclear. Here, Pdk1, a member of the AGC kinase family, was conditionally disrupted by crossing an Emx1-Cre mouse line with a Pdk1fl/fl line. The loss of Pdk1 led to a shorter cell cycle accompanied by increased RGC proliferation specifically at late rather than early/middle neurogenic stages, which was attributed to impaired lengthening of G1 phase. Coincidently, apical-to-basal interkinetic nuclear migration was accelerated in Pdk1 cKO cortices. Consequently, we detected an increased neuronal output at P0. We further showed the significant upregulation of the cell cycle regulator cyclin D1 and its activator Myc in the cKO cortices relative to those of control animals. Overall, we have identified a novel role for PDK1 in cortical neurogenesis. PDK1 functions as an upstream regulator of the Myc-cyclin D1 pathway to control the lengthening of G1 phase and the balance between RGC proliferation and differentiation.