New mechanism driving cortical gyrification and hydrocephalus in mice - scope for novel small-molecule therapy
New mechanism driving cortical gyrification and hydrocephalus in mice - scope for novel small-molecule therapy
We identified that PI3K over-activation resulted in disruption of cell adhesion at the neural-ependymal transition zone causing ventriculomegaly, and also in differential proliferation of progenitors, triggering abnormal cortical folding (effect of genotype). In mutant mice, an FDA-approved small-molecule drug, verteporfin, attenuated these anomalies (effect of drug), leading to reduction in gyrification severity as well as ventriculomegaly. This in turn prevented advancement towards hydrocephalus in these mice. These findings also promoted repurposing of available therapeutics towards treating neurodevelopmental disorders.
(a) Schematic of PI3K-AKT-MTOR pathway, its connection with Yap signaling and mode of verteporfin action. The activity of the PI3K enzyme (dimer of catalytic and regulatory subunits) initiates the PI3K-AKT-MTOR pathway cascade. In parallel, downstream of the Hippo pathway, Yap binds to transcriptional regulator proteins in the nucleus, to facilitate cell growth and proliferation. Activation of Hippo pathway results in translocation of nuclear Yap to cytoplasm through phosphorylation. Cytoplasmic Yap, in turn, promotes cell adhesion. The activating Pik3ca mutation results in Yap translocation from cytoplasm to nucleus, possibly via Pdk1. In this study, verteporfin, a nuclear Yap inhibitor, restored cytoplasmic Yap. (b,c) Schematics summarizing main findings of the paper: PI3K over-activation resulted in disruption of cell adhesion at the neural-ependymal transition zone causing ventriculomegaly, and also in differential proliferation of progenitors, thus triggering the gyrification sequence cascade (effect of genotype). In mutant mice, verteporfin attenuated these anomalies (effect of drug), leading to reduction in gyrification severity as well as ventriculomegaly. Area within the yellow dashed boxes in the top rows of (b) and (c) is magnified in the respective bottom rows. Color coding for elements in (b) and (c) is explained in the figure ‘key’. vz/svz, ventricular/subventricular zone.
