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中的突变扰乱了小鼠的神经元迁移，并与人类的神经发育疾病有关。

脊椎动物大脑的形成需要神经元的生成，迁移，分化和存活。干扰这些关键细胞事件的遗传突变可导致端脑畸形，从而为大脑发育提供了分子窗口。在这里我们报告鉴定的N-乙基-N-亚硝基脲诱导的小鼠突变体的特征是海马锥体细胞层破裂，归因于神经元迁移的缺陷。我们表明，这是由Vps15的一个亚型突变引起的，该突变扰乱了内体-溶酶体的运输和自噬，导致Nischarin的上调，从而抑制了Pak1信号传导。Vps15的完全消融导致自噬底物的积累，细胞凋亡的诱导和严重的皮质萎缩。最后，我们报道了VPS15的突变与人类的皮质萎缩和癫痫症有关。这些数据突出了Vps15-Vps34复合体和Nischarin-Pak1信号枢纽在端脑发育中的重要性。