title: Ets transcription factors control epithelial maturation and transit and crypt-villus morphogenesis in the mammalian intestine.
abstract: Members of the Ets transcription factor family are widely expressed in both the developing and mature mammalian intestine, but their biological functions remain primarily uncharacterized. We used a dominant repressor transgene approach to probe the function of epithelial Ets factors in the homeostasis of the crypt-villus unit, the functional unit of the small intestine. We show that targeted expression in small intestinal epithelium of a fusion protein composed of the Engrailed repressor domain and the Erm DNA-binding domain (En/Erm) results in marked disruption of normal crypt-villus homeostasis, including a cell-autonomous disturbance of epithelial maturation, increased epithelial transit, severe villus dysmorphogenesis, and crypt dysmorphogenesis. The epithelial maturation disturbance is independent of the regulation of TGFbetaRII levels, in contrast to Ets-mediated epithelial differentiation during development; rather, regulation of Cdx2 expression may play a role. The villus dysmorphogenesis is independent of alterations in the crypt-villus boundary and inappropriate beta-catenin activation, and thus appears to represent a new mechanism controlling villus architectural organization. An Analysis of animals mosaic for En/Erm expression suggests that crypt nonautonomous mechanisms underlie the crypt dysmorphogenesis phenotype. Our studies thus uncover novel Ets-regulated pathways of intestinal homeostasis in vivo. Interestingly, the overall En/Erm phenotype of disturbed crypt-villus homeostasis is consistent with recently identified Ets function(s) in the restriction of intestinal epithelial tumorigenesis.
authors.affiliation: Department of Pathology, University of Colorado Denver, Anschutz Medical Center, PO Box 6511, MS 8104, Aurora CO 80045, USA. paul.jedlicka@ucdenver.edu
authors.forename: Paul
authors.initials: P
authors.lastname: Jedlicka
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Sui
authors.forename: Lori
authors.initials: L
authors.lastname: Sussel
authors.forename: Arthur
authors.initials: A
authors.lastname: Gutierrez-Hartmann
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D020895:Enterocytes / Q000166:cytology* / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D014162:Transfection
chemical_list: D050783:Proto-Oncogene Proteins c-ets