TY - JOUR AB - 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. AU - Gstrein, Thomas AU - Edwards, Andrew AU - Přistoupilová, Anna AU - Leca, Ines AU - Breuss, Martin AU - Pilat Carotta, Sandra AU - Hansen, Andi H AU - Tripathy, Ratna AU - Traunbauer, Anna AU - Hochstoeger, Tobias AU - Rosoklija, Gavril AU - Repic, Marco AU - Landler, Lukas AU - Stránecký, Viktor AU - Dürnberger, Gerhard AU - Keane, Thomas AU - Zuber, Johannes AU - Adams, David AU - Flint, Jonathan AU - Honzik, Tomas AU - Gut, Marta AU - Beltran, Sergi AU - Mechtler, Karl AU - Sherr, Elliott AU - Kmoch, Stanislav AU - Gut, Ivo AU - Keays, David ID - 547 IS - 2 JF - Nature Neuroscience TI - Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans VL - 21 ER -