The small GTPase cell division cycle 42 (CDC42) plays essential roles in neurogenesis and brain development. Previously, using murine embryonic P19 cells as a model system, we showed that CDC42 stimulates mTOR complex 1 (mTORC1) activity and thereby up-regulates transcription factors required for the formation of neural progenitor cells. However, paradoxically, although endogenous CDC42 is required for both the initial transition of undifferentiated P19 cells to neural progenitors and their ultimate terminal differentiation into neurons, ectopic CDC42 overexpression promotes only the first stage of neurogenesis (i.e. the formation of neuroprogenitors) and not the second phase (differentiation into neurons). Here, using both P19 cells and mouse embryonic stem cells, we resolve this paradox, demonstrating that two splice variants of CDC42, differing only in nine amino acid residues in their very C-terminal regions, play distinct roles in neurogenesis. We found that a CDC42 splice variant that has a ubiquitous tissue distribution, termed here as CDC42u, specifically drives the formation of neuroprogenitor cells, whereas a brain-specific CDC42 variant, CDC42b, is essential for promoting the transition of neuroprogenitor cells to neurons. We further show that the specific roles of CDC42u and CDC42b in neurogenesis are due to their opposing effects on mTORC1 activity. Specifically, CDC42u stimulated mTORC1 activity and thereby induced neuroprogenitor formation, whereas CDC42b worked together with activated CDC42-associated kinase (ACK) in down-regulating mTOR expression and promoting neuronal differentiation. These findings highlight the remarkable functional specificities of two highly similar CDC42 splice variants in regulating distinct stages of neurogenesis.

中文翻译：

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Cdc42的两种剪接变体形式在神经发生中发挥独特的基本功能。

小GTPase细胞分裂周期42（CDC42）在神经发生和大脑发育中起重要作用。以前，使用鼠类胚胎P19细胞作为模型系统，我们显示CDC42刺激mTOR复合物1（mTORC1）活性，从而上调形成神经祖细胞所需的转录因子。然而，自相矛盾的是，尽管未分化的P19细胞向神经祖细胞的初始过渡及其最终向神经元的终末分化都需要内源性CDC42，但异位CDC42的过表达仅促进神经发生的第一阶段（即神经祖细胞的形成），而不是第二阶段。阶段（分化为神经元）。在这里，我们同时使用P19细胞和小鼠胚胎干细胞，解决了这一悖论，证明了CDC42的两个剪接变体，仅在其C末端区域的9个氨基酸残基不同，在神经发生中起不同的作用。我们发现具有无处不在的组织分布的CDC42剪接变体（此处称为CDC42u）特异性地驱动神经祖细胞的形成，而脑特异性CDC42变体CDC42b对于促进神经祖细胞向神经元的过渡至关重要。我们进一步表明CDC42u和CDC42b在神经发生中的特定作用是由于它们对mTORC1活性的相反作用。具体而言，CDC42u刺激了mTORC1的活性，从而诱导了神经祖细胞的形成，而CDC42b与活化的CDC42相关的激酶（ACK）一起在下调mTOR表达和促进神经元分化中发挥了作用。