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

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.

SUBMITTER: Gstrein T

PROVIDER: S-EPMC5897053 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Gstrein Thomas T Edwards Andrew A Přistoupilová Anna A Leca Ines I Breuss Martin M Pilat-Carotta Sandra S Hansen Andi H AH Tripathy Ratna R Traunbauer Anna K AK Hochstoeger Tobias T Rosoklija Gavril G Repic Marco M Landler Lukas L Stránecký Viktor V Dürnberger Gerhard G Keane Thomas M TM Zuber Johannes J Adams David J DJ Flint Jonathan J Honzik Tomas T Gut Marta M Beltran Sergi S Mechtler Karl K Sherr Elliott E Kmoch Stanislav S Gut Ivo I Keays David A DA

Nature neuroscience 20180108 2

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 ...[more]

PMID: 29311744

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Project description:Manganese (Mn) is essential for neuronal health but neurotoxic in excess. Mn levels vary across brain regions and neurodevelopment. While Mn requirements during infanthood and childhood are significantly higher than in adulthood, the relative vulnerability to excess extracellular Mn across human neuronal developmental time and between distinct neural lineages is unknown. Neurological disease is associated with changes in brain Mn homeostasis and pathology associated with Mn neurotoxicity is not uniform across brain regions. For example, mutations associated with Huntington's disease (HD) decrease Mn bioavailability and increase resistance to Mn cytotoxicity in human and mouse striatal neuronal progenitors. Here, we sought to compare the differences in Mn cytotoxicity between control and HD human-induced pluripotent stem cells (hiPSCs)-derived neuroprogenitor cells (NPCs) and maturing neurons. We hypothesized that there would be differences in Mn sensitivity between lineages and developmental stages. However, we found that the different NPC lineage specific media substantially influenced Mn cytotoxicity in the hiPSC derived human NPCs and did so consistently even in a non-human cell line. This limited the ability to determine which human neuronal sub-types were more sensitive to Mn. Nonetheless, we compared within neuronal subtypes and developmental stage the sensitivity to Mn cytotoxicity between control and HD patient derived neuronal lineages. Consistent with studies in other striatal model systems the HD genotype was associated with resistance to Mn cytotoxicity in human striatal NPCs. In addition, we report an HD genotype-dependent resistance to Mn cytotoxicity in cortical NPCs and hiPSCs. Unexpectedly, the HD genotype conferred increased sensitivity to Mn in early post-mitotic midbrain neurons but had no effect on Mn sensitivity in midbrain NPCs or post-mitotic cortical neurons. Overall, our data suggest that sensitivity to Mn cytotoxicity is influenced by HD genotype in a human neuronal lineage type and stage of development dependent manner.

Dataset Information

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

Publications

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

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