Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans Journal Article

Author(s): Gstrein, Thomas; Edwards, Andrew; Přistoupilová, Anna; Leca, Ines; Breuss, Martin; Pilat-Carotta, Sandra; Hansen, Andi H; Tripathy, Ratna; Traunbauer, Anna K; Hochstoeger, Tobias; Rosoklija, Gavril; Repic, Marco; Landler, Lukas; Stránecký, Viktor; Dürnberger, Gerhard; Keane, Thomas M; Zuber, Johannes; Adams, David J; Flint, Jonathan; Honzik, Tomas; Gut, Marta; Beltran, Sergi; Mechtler, Karl; Sherr, Elliott; Kmoch, Stanislav; Gut, Ivo; Keays, David A
Article Title: Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans
Affiliation IST Austria
Abstract: 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.
Journal Title: Nature Neuroscience
Volume: 21
Issue 2
ISSN: 10976256
Publisher: Nature Publishing Group  
Date Published: 2018-06-06
Start Page: 207
End Page: 217
DOI: 10.1038/s41593-017-0053-5
Notes: We also acknowledge the input of P. Potter and S. Wells from the mutagenesis program at MRC Harwell and the MRC funding that underpinned it (MC U142684172). We are indebted to R. Williams for modeling the VPS15 human mutation. We also thank the transgenic, bio-optics, proteomic and graphics services groups at the IMP/IMBA. We thank The National Center for Medical Genomics (LM2015091) for providing allelic frequencies in ethnically matched populations (project CZ.02.1.01/0.0/0.0/16_013/0001634). We thank Boehringer Ingelheim and the FWF for funding this research (D.A.K., I914, P24267). The human studies were funded by the European Community’s 7th Framework Program (FP7/2007-2013). S.K., A.P. and V.S. were supported by institutional programs of Charles University in Prague (UNCE 204011, PROGRES-Q26/LF1 and SVV 260367/2017). We acknowledge grants 15-28208A and RVO-VFN 64165 from the Ministry of Health of the Czech Republic and the project LQ1604 NPU II from the Ministry of Education.
Open access: no