Altered intestinal epithelial homeostasis in mice with intestine-specific deletion of the Krüppel-like factor 4 gene.
The zinc finger transcription factor, Krüppel-like factor 4 (KLF4), is expressed in the post-mitotic, differentiated epithelial cells lining the intestinal tract and exhibits a tumor suppressive effect on intestinal tumorigenesis. Here we report a role for KLF4 in maintaining homeostasis of intestinal epithelial cells. Mice with conditional ablation of the Klf4 gene from the intestinal epithelium were viable. However, both the rates of proliferation and migration of epithelial cells were increased in the small intestine of mutant mice. In addition, the brush-border alkaline phosphatase was reduced as was expression of ephrine-B1 in the small intestine, resulting in mispositioning of Paneth cells to the upper crypt region. In the colon of mutant mice, there was a reduction of the differentiation marker, carbonic anhydrase-1, and failure of differentiation of goblet cells. Mechanistically, deletion of Klf4 from the intestine resulted in activation of genes in the Wnt pathway and reduction in expression of genes encoding regulators of differentiation. Taken together, these data provide new insights into the function of KLF4 in regulating postnatal proliferation, migration, differentiation, and positioning of intestinal epithelial cells and demonstrate an essential role for KLF4 in maintaining normal intestinal epithelial homeostasis in vivo.
Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Amr M
AM
Ghaleb
Beth B
BB
McConnell
Klaus H
KH
Kaestner
Vincent W
VW
Yang
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D024401:Carbonic Anhydrase I / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement; D049109:Cell Proliferation; D036387:Ephrin-B1 / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology*; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006652:Histological Techniques; D006706:Homeostasis / Q000502:physiology*; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000502:physiology*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D016133:Polymerase Chain Reaction
D036387:Ephrin-B1; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D000469:Alkaline Phosphatase; D024401:Carbonic Anhydrase I; D001973:Bromodeoxyuridine