Submitted on October 7, 2008
Revised on April 23, 2009
Accepted on April 23, 2009
Fibroblast Growth Factor Receptor-3 Regulates Paneth Cell Lineage Allocation and Accrual of Epithelial Stem Cells During Murine Intestinal Development
Alda Vidrich1, Jenny M Buzan1, Brooks Brodrick1, Chibuzo Ilo1, Leigh Bradley1, Kirstin Skaar Fendig1, Thomas Sturgill, and Steven M. Cohn2*
1 University of Virginia
2 Univ. of Virginia Medical School
* To whom correspondence should be addressed. E-mail: sc6w{at}virginia.edu.
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 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 when compared with wild type littermates. A marked deficit in allocation of progenitor cells to Paneth cell differentiation was noted although all of the principle epithelial lineages were represented in FGFR-3-/- mice. The total cellular content and nuclear localization of 
-catenin protein were reduced in FGFR-3-/- mice, as was expression of Cyclin D1 and MMP-7, major downstream targets of -catenin/Tcf-4 signaling. Activation of FGFR-3 in Caco2 cells, an intestinal epithelial cell line, abrogated the fall in -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 -catenin/Tcf-4 dependent and independent pathways.
