Supplementary Figure 10: Model showing the effect of Vps15 mutations on neuronal migration and cell survival | Nature Neuroscience

Supplementary Figure 10: Model showing the effect of Vps15 mutations on neuronal migration and cell survival

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

Supplementary Figure 10

Under wild-type conditions Vps15 acts in a complex with Vps34 and Beclin1 catalyzing the formation of the phospholipid PI(3)P at endosomes and autophagosomes. The splice site mutation in the Marble mouse is a hypomorph, reducing the levels of the Vps15/Vps34 complex which impairs endosome (E) to lysosome (L) trafficking. As a consequence, Nischarin, a protein that binds PI(3)P and is localized to the endosome, is upregulated in Marble mutants. Nischarin inhibits Pak1 phosphorylation, which is known to influence microtubule dynamics through the phosphorylation of tubulin cofactor B and the actin cytoskeleton by activating LIM kinase. We propose that perturbation of this pathway causes the neuronal migration defect in Marble animals. If Vps15 is deleted in neurons, autophagy progression is blocked leading to the accumulation of p62 positive substrates. This in turn is associated with caspase induced cell death and severe cortical atrophy.

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