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MUCOSAL BIOLOGY

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

¹Digestive Health Center of Excellence and ²Department of Pharmacology, University of Virginia, Charlottesville, Virginia

Submitted 7 October 2008 ; accepted in final form 23 April 2009

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.

fibroblast growth factors; β-catenin; T cell factor-4; intestinal morphogenesis