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PI3K-Yap activity drives cortical gyrification and hydrocephalus in mice

ABSTRACT: Mammalian brain evolved through several transitions between gyrencephaly and lissencephaly. Mechanisms generating gyrified or smooth brain are incompletely understood. Here we demonstrate that a short embryonic pulse of activating mutations in Pik3ca, the catalytic subunit of PI3K enzyme is sufficient to cause mouse cortical gyrification. We demonstrate that this gyrification phenotype is initiated by subtle focal regulation of apical cell adhesion and proliferation via PI3K-dependent localization of Yap protein. Treatment with verteporfin (Drug) a nuclear Yap inhibitor, attenuated over-proliferation and adhesion abnormalities, and subsequently gyrification. The purpose of this study was to compare the control and mutant mouse transcriptome, and their respective effect upon verteprofin treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE127896 | GEO | 2019/05/15

REPOSITORIES: GEO

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PI3K-Yap activity drives cortical gyrification and hydrocephalus in mice

Project description:PI3K-Yap activity drives cortical gyrification and hydrocephalus in mice

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Inhibition of PIK3CA by miR-203a-3p reduces hypertrophic scar formation via PI3K/AKT/mTOR signaling pathway

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Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival [ChIPseq]

Project description:Background—YAP, the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEAD sequence specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. Methods and Results—To identify genes directly regulated by YAP in cardiomyocytes, we combined differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase (PI3K), as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. We validated YAP and TEAD occupancy of a conserved enhancer within the first intron of Pik3cb, and show that this enhancer drives YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the PI3K-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened the YAP mitogenic activity. Reciprocally, Yap loss-of-function impaired heart function and reduced cardiomyocyte proliferation and survival, all of which were significantly rescued by AAV-mediated Pik3cb expression. Conclusion—Pik3cb is a crucial direct target of YAP, through which the YAP activates PI3K-AKT pathway and regulates cardiomyocyte proliferation and survival. Yap wild type ChIPseq and input

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Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival [microarray]

2015-02-20 | E-GEOD-57718 | biostudies-arrayexpress

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Overexpression of PIK3CA in head and neck squamous cell carcinoma is associated with poor outcome and activation of the YAP pathway

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