title: Cdx2 levels modulate intestinal epithelium maturity and Paneth cell development.
abstract: OBJECTIVE
  Caudal-related homeobox protein 2 (Cdx2) is an intestine-specific transcription factor that is important for intestinal development and intestine-specific gene expression. Cdx2 regulates intestinal cell-cell adhesion, proliferation, and the transcriptional activities of Wnt and β-catenin in cell culture systems. We generated transgenic mice that overexpress Cdx2 in the small intestinal and colonic epithelium to investigate the role of Cdx2 in differentiation and function of the intestinal epithelium.
  
  
  METHODS
  We established 4 different lines of villin-Cdx2 transgenic mice. Intestines were collected from infant, 3-month old, and wild-type mice. Genes of interest and cell lineage markers were examined by polymerase chain reaction and immunohistochemistry.
  
  
  RESULTS
  Villin-Cdx2 transgenic mice had complex phenotypes that were associated with transgene expression levels. The 2 lines that had the greatest levels of transgene expression had significant, preweaning failure to grow and death; these were the result of early epithelial maturation and alterations in nutrient digestion and absorption. Fat malabsorption was a prominent feature. Other effects associated with the transgene expression included loss of Paneth cell markers, increases in goblet cells, and migration of proliferating, EphB2-expressing cells to the crypt base. Loss of Paneth cell markers was associated with reduced nuclear localization of β-catenin but not homeotic posteriorization of the epithelium by Cdx2.
  
  
  CONCLUSIONS
  Overexpression of Cdx2 in the small intestine is associated with reduced post-natal growth, early epithelial maturation, alterations in crypt base organization, and changes in Paneth and goblet cell lineages. Cdx2 is a critical regulator not only of intestine-specific genes, but also processes that determine epithelial maturity and function.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. lynchj@mail.med.upenn.edu
authors.forename: Mary Ann S
authors.initials: MA
authors.lastname: Crissey
authors.forename: Rong-Jun
authors.initials: RJ
authors.lastname: Guo
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Funakoshi
authors.forename: Jianping
authors.initials: J
authors.lastname: Kong
authors.forename: Jesse
authors.initials: J
authors.lastname: Liu
authors.forename: John P
authors.initials: JP
authors.lastname: Lynch
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D020397:Goblet Cells / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000502:physiology*; D008286:Malabsorption Syndromes / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D009030:Mosaicism; D019879:Paneth Cells / Q000378:metabolism / Q000502:physiology*; D036183:Receptor, EphB2 / Q000032:analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000032:analysis
chemical_list: D015415:Biomarkers; D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D008840:Microfilament Proteins; D014157:Transcription Factors; D051176:beta Catenin; C026615:villin; D036183:Receptor, EphB2