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

Cell Rep. 2022 Jan 11;38(2):110009. doi: 10.1016/j.celrep.2021.110009.


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.

Keywords: Cdc42; Hippo signaling; cell fate; intestinal stem cells; mTOR signaling; mouse model; polarity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Differentiation / physiology
  • Cell Lineage
  • Cell Polarity / genetics
  • Cell Polarity / physiology*
  • Cell Proliferation / physiology
  • Epidermal Growth Factor / metabolism
  • Female
  • Hippo Signaling Pathway / physiology
  • Intestines / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction / physiology
  • Stem Cells / metabolism*
  • Stem Cells / physiology
  • TOR Serine-Threonine Kinases / metabolism
  • Wnt Signaling Pathway / physiology
  • cdc42 GTP-Binding Protein / metabolism*
  • cdc42 GTP-Binding Protein / physiology


  • Adaptor Proteins, Signal Transducing
  • Cdc42 protein, mouse
  • Epidermal Growth Factor
  • TOR Serine-Threonine Kinases
  • cdc42 GTP-Binding Protein