Abstract
Mechanisms driving the initiation of brain folding are incompletely understood. We have previously characterized mouse models recapitulating human PIK3CA-related brain overgrowth, epilepsy, dysplastic gyrification and hydrocephalus (Roy et al., 2015). Using the same, highly regulatable brain-specific model, here we report PI3K-dependent mechanisms underlying gyrification of the normally smooth mouse cortex, and hydrocephalus. We demonstrate that a brief embryonic Pik3ca activation was sufficient to drive subtle changes in apical cell adhesion and subcellular Yap translocation, causing focal proliferation and subsequent initiation of the stereotypic 'gyrification sequence', seen in naturally gyrencephalic mammals. Treatment with verteporfin, a nuclear Yap inhibitor, restored apical surface integrity, normalized proliferation, attenuated gyrification and rescued the associated hydrocephalus, highlighting the interrelated role of regulated PI3K-Yap signaling in normal neural-ependymal development. Our data defines apical cell-adhesion as the earliest known substrate for cortical gyrification. In addition, our preclinical results support the testing of Yap-related small-molecule therapeutics for developmental hydrocephalus.