The formation of the vertebrate brain requires the generation, migration, differentiation and survival of neurons. Genetic mutations that perturb these critical cellular events can result in malformations of the telencephalon, providing a molecular window into brain development. Here we report the identification of an N-ethyl-N-nitrosourea-induced mouse mutant characterized by a fractured hippocampal pyramidal cell layer, attributable to defects in neuronal migration. We show that this is caused by a hypomorphic mutation in Vps15 that perturbs endosomal-lysosomal trafficking and autophagy, resulting in an upregulation of Nischarin, which inhibits Pak1 signaling. The complete ablation of Vps15 results in the accumulation of autophagic substrates, the induction of apoptosis and severe cortical atrophy. Finally, we report that mutations in VPS15 are associated with cortical atrophy and epilepsy in humans. These data highlight the importance of the Vps15-Vps34 complex and the Nischarin-Pak1 signaling hub in the development of the telencephalon.

中文翻译：

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Vps15 突变会扰乱小鼠神经元迁移，并与人类神经发育疾病相关。


脊椎动物大脑的形成需要神经元的产生、迁移、分化和存活。扰乱这些关键细胞事件的基因突变可能导致端脑畸形，从而为大脑发育提供了一个分子窗口。在这里，我们报告了 N-乙基-N-亚硝基脲诱导的小鼠突变体的鉴定，其特征是海马锥体细胞层断裂，归因于神经元迁移缺陷。我们发现这是由 Vps15 的亚等位性突变引起的，该突变扰乱了内体-溶酶体运输和自噬，导致 Nischarin 上调，从而抑制 Pak1 信号传导。 Vps15的完全消除导致自噬底物的积累、诱导细胞凋亡和严重的皮质萎缩。最后，我们报告 VPS15 突变与人类皮质萎缩和癫痫有关。这些数据强调了 Vps15-Vps34 复合体和 Nischarin-Pak1 信号中枢在端脑发育中的重要性。