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Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans.
- Source :
-
Nature neuroscience [Nat Neurosci] 2018 Feb; Vol. 21 (2), pp. 207-217. Date of Electronic Publication: 2018 Jan 08. - Publication Year :
- 2018
-
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.
- Subjects :
- Alkylating Agents toxicity
Animals
Animals, Newborn
Atrophy chemically induced
Atrophy genetics
Atrophy pathology
Autophagy drug effects
Autophagy genetics
Brain drug effects
Brain pathology
Cell Movement drug effects
Disease Models, Animal
Embryo, Mammalian
Ethylnitrosourea toxicity
Female
Gene Expression Regulation, Developmental genetics
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurons drug effects
Neurons ultrastructure
Signal Transduction drug effects
Signal Transduction genetics
Vacuolar Proton-Translocating ATPases drug effects
Cell Movement genetics
Gene Expression Regulation, Developmental drug effects
Mutation drug effects
Neurodevelopmental Disorders chemically induced
Neurodevelopmental Disorders diagnostic imaging
Neurodevelopmental Disorders genetics
Neurodevelopmental Disorders pathology
Neurons pathology
Vacuolar Proton-Translocating ATPases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1726
- Volume :
- 21
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Nature neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 29311744
- Full Text :
- https://doi.org/10.1038/s41593-017-0053-5