Fibroblast growth factor receptor-3 regulates Paneth cell lineage allocation and accrual of epithelial stem cells during murine intestinal development

Alda Vidrich, Jenny M. Buzan, Brooks Brodrick, Chibuzo Ilo, Leigh Bradley, Kirstin Skaar Fendig, Thomas Sturgill, Steven M. Cohn

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Fibroblast growth factor receptor 3 (FGFR-3) is expressed in the lower crypt epithelium, where stem cells of the intestine reside. The role of FGFR-3 signaling in regulating features of intestinal morphogenesis was examined in FGFR-3-null (FGFR-3-/-) mice. FGFR-3-/- mice had only about half the number of intestinal crypts and a marked decrease in the number of functional clonogenic stem cells, as assessed by an in vivo microcolony-forming assay, compared with wild-type littermates. A marked deficit in allocation of progenitor cells to Paneth cell differentiation was noted, although all the principal epithelial lineages were represented in FGFR-3 -/- mice. The total cellular content and nuclear localization of β-catenin protein were reduced in FGFR-3-/- mice, as was expression of cyclin D1 and matrix metalloproteinase-7, major downstream targets of β-catenin/T cell factor-4 (Tcf-4) signaling. Activation of FGFR-3 in Caco-2 cells, an intestinal epithelial cell line, abrogated the fall in β-catenin/Tcf-4 signaling activity that is normally observed in these cells as cultures become progressively more confluent. These findings are consistent with the hypothesis that, during intestinal development, FGFR-3 signaling regulates crypt epithelial stem cell expansion and crypt morphogenesis, as well as Paneth cell lineage specification, through β-catenin/Tcf-4-dependent and -independent pathways.

Original languageEnglish (US)
Pages (from-to)G168-G178
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume297
Issue number1
DOIs
StatePublished - Jul 2009

Keywords

  • Fibroblast growth factors
  • Intestinal morphogenesis
  • T cell factor-4
  • β-catenin

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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