CDC42 controlled apical-basal polarity regulates intestinal stem cell to transit amplifying cell fate transition via YAP-EGF-mTOR signaling

Epithelial polarity is controlled by a polarity machinery that includes Rho GTPase CDC42 and Scribble/PAR. By using intestinal stem cell (ISC)-specific deletion of CDC42 in olfactomedin-4 (Olfm4)-internal ribosome entry site (IRES)-EGFP/CreERT2;CDC42flox/flox mice, we find that CDC42 loss initiated in the ISCs causes a drastic hyperproliferation of transit amplifying (TA) cells and disrupts epithelial polarity. CDC42-null crypts display expanded TA cell and diminished ISC populations, accompanied by elevated Hippo signaling via YAP/TAZ-Ereg (yes-associated protein/WW domain-containing transcription regulator protein 1-epiregulin) and mechanistic target of rapamycin (mTOR) activation, independent from canonical Wnt signaling. YAP/TAZ conditional knockout (KO) restores the balance of ISC/TA cell populations and crypt proliferation but does not rescue the polarity in CDC42-null small intestine. mTOR or epidermal growth factor receptor (EGFR) inhibitor treatment of CDC42 KO mice exhibits similar rescuing effects without affecting YAP/TAZ signaling. Inducible ablation of Scribble in intestinal epithelial cells mimics that of CDC42 KO defects, including crypt hyperplasia and Hippo signaling activation. Mammalian epithelial polarity regulates ISC/TA cell fate and proliferation via a Hippo-Ereg-mTOR cascade. [Display omitted] •Cdc42 deletion in mouse ISCs causes defective polarity and hyperplasia of crypts•CDC42 regulates polarity-Hippo signaling independent of canonical Wnt signaling•Ereg and mTOR mediate CDC42-YAP signaling in the crypts•Apical polarity-YAP signaling maintains ISC and TA cell fate balance Zhang et al. discover that CDC42-dependent polarity signaling regulates ISC and TA cell fate and proliferation via a YAP-Ereg-mTOR cascade in the small intestine. This study shows that mammalian epithelial polarity-controlled Hippo signaling is central to cell fate balance between ISC and TA cells and intestinal crypt proliferation.