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.

CNAG CRG Centre for Genomic Regulation Barcelona Spain

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague Czech Republic

Institute for Molecular Biotechnology Vienna Austria

Institute of Human Genetics University of California San Francisco San Francisco CA USA

Institute of Inherited Metabolic Disorders Charles University Prague Czech Republic

Institute of Molecular Pathology Vienna Austria

Universitat Pompeu Fabra Barcelona Spain

Wellcome Trust Center for Human Genetics Oxford UK

Wellcome Trust Sanger Institute Hinxton Cambridgeshire UK

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Nat Neurosci. 2018 Aug;21(8):1139. doi: 10.1038/s41593-018-0170-9. PubMed

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