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

T. Gstrein, A. Edwards, A. Přistoupilová, I. Leca, M. Breuss, S. Pilat-Carotta, AH. Hansen, R. Tripathy, AK. Traunbauer, T. Hochstoeger, G. Rosoklija, M. Repic, L. Landler, V. Stránecký, G. Dürnberger, TM. Keane, J. Zuber, DJ. Adams, J. Flint, T....

. 2018 ; 21 (2) : 207-217. [pub] 20180108

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc19028633

Grantová podpora
R01 NS058721 NINDS NIH HHS - United States
NV15-28208A MZ0 CEP - Centrální evidence projektů

Digitální knihovna NLK
Plný text - Článek
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E-zdroje Online Plný text

NLK ProQuest Central od 2000-01-01 do Před 1 rokem
Health & Medicine (ProQuest) od 2000-01-01 do Před 1 rokem
Psychology Database (ProQuest) od 2000-01-01 do Před 1 rokem

Odkazy

PubMed 29311744
DOI 10.1038/s41593-017-0053-5
Knihovny.cz E-zdroje

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.

Citace poskytuje Crossref.org

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