title: Cdc42 coordinates proliferation, polarity, migration, and differentiation of small intestinal epithelial cells in mice.
abstract: OBJECTIVE
  Cdc42 is a Rho GTPase that regulates diverse cellular functions, including proliferation, differentiation, migration, and polarity. In the intestinal epithelium, a balance among these events maintains homeostasis. We used genetic techniques to investigate the role of Cdc42 in intestinal homeostasis and its mechanisms.
  
  
  METHODS
  We disrupted Cdc42 specifically in intestinal epithelial cells by creating Cdc42flox/flox-villin-Cre+ and Cdc42flox/flox-Rosa26-CreER+ mice. We collected intestinal and other tissues, and analyzed their cellular, molecular, morphologic, and physiologic features, compared with the respective heterozygous mice.
  
  
  RESULTS
  In all mutant mice studied, the intestinal epithelium had gross hyperplasia, crypt enlargement, microvilli inclusion, and abnormal epithelial permeability. Cdc42 deficiency resulted in defective Paneth cell differentiation and localization without affecting the differentiation of other cell lineages. In mutant intestinal crypts, proliferating stem and progenitor cells increased, compared with control mice, resulting in increased crypt depth. Cdc42 deficiency increased migration of stem and progenitor cells along the villi, caused a mild defect in the apical junction orientation, and impaired intestinal epithelium polarity, which can contribute to the observed defective intestinal permeability. The intestinal epithelium of the Cdc42flox/flox-villin-Cre+ and Cdc42flox/flox-Rosa26-CreER+ mice appeared similar to that of patients with microvillus inclusion disease. In the digestive track, loss of Cdc42 also resulted in crypt hyperplasia in the colon, but not the stomach.
  
  
  CONCLUSIONS
  Cdc42 regulates proliferation, polarity, migration, and differentiation of intestinal epithelial cells in mice and maintains intestine epithelial barrier and homeostasis. Defects in Cdc42 signaling could be associated with microvillus inclusion disease.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pharmacy, Faculty of Chemistry, P. Catholic University of Chile, Santiago, Chile.
authors.forename: Jaime
authors.initials: J
authors.lastname: Melendez
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Leesa
authors.initials: L
authors.lastname: Sampson
authors.forename: Shailaja
authors.initials: S
authors.lastname: Akunuru
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Han
authors.forename: Jefferson
authors.initials: J
authors.lastname: Vallance
authors.forename: David
authors.initials: D
authors.lastname: Witte
authors.forename: Noah
authors.initials: N
authors.lastname: Shroyer
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation; D007413:Intestinal Mucosa / Q000166:cytology*; D007421:Intestine, Small / Q000166:cytology*; D051379:Mice; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*
chemical_list: C581598:Cdc42 protein, mouse; D020764:cdc42 GTP-Binding Protein
keywords: BrdU; CCHMC; Cincinnati Children’s Hospital Medical Center; Conditional Deletion; ISC; KO; MDCK; MVID; MVID Model; Madin-Darby canine kidney; PBS; Polarity; Proliferation; aPKC; atypical protein kinase C; bromodeoxyuridine; intestinal stem cell; knockout; microvillus inclusion disease; phosphate-buffered saline; vil; villin