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.
Highlights
The mammalian brain has evolved through multiple transitions between gyrencephaly and lissencephaly (Lewitus et al, 2014)
Cortical expansion and gyrification have been implicated in the evolution of human cognition; and dysplastic gyrification is associated with numerous neurodevelopmental disorders including hydrocephalus (Jimenez et al, 2014; Guerra et al, 2015; Gregory et al, 2016; Parrini et al, 2016; Borrell, 2018)
Cortical gyrification or its absence is an essential feature of mammalian brain evolution but the mechanisms driving cortical folding, its initiation, are poorly understood (Borrell, 2018)
Summary
The mammalian brain has evolved through multiple transitions between gyrencephaly and lissencephaly (Lewitus et al, 2014). PI3K activation disrupted apical junctions and caused ectopic subcellular translocation of Yap leading to neural proliferation and gyrification, as well as abnormal ependymal development and hydrocephalus Both the gyrification and hydrocephalus phenotypes were attenuated in the mutant mice by treatment with verteporfin (US Food and Drug Administration, 2000; Schmidt-Erfurth and Hasan, 2000; Liu-Chittenden et al, 2012), a nuclear Yap inhibitor. These results demonstrate that the PI3K/Hippo-Yap pathway is finely tuned to regulate cell adhesion and proliferation along the apical lining of the forebrain to maintain the lissencephalic mouse brain. Subtle alterations in this pathway during the mid-neurogenic phase have dramatic consequences for the cytoarchitecture of forebrain ventricular linings and the interrelated processes of neurogenesis, gyrification and ependymal development
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