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Fibroblast Growth Factor Receptor 3 (FGFR3) modulates Paneth cell lineage allocation through a β‐catenin/Tcf‐4 dependent signaling mechanism
Author(s) -
Brodrick Brooks Barrett,
Vidrich Alda,
Buzan Jenny,
Bradley Leigh,
Cohn Steven M.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.359.1
Subject(s) - paneth cell , microbiology and biotechnology , biology , fibroblast growth factor , cellular differentiation , stem cell factor , stem cell , receptor tyrosine kinase , signal transduction , receptor , progenitor cell , endocrinology , biochemistry , small intestine , gene
Fibroblast growth factor receptors are receptor tyrosine kinases that mediate cellular growth and differentiation during normal gut development and injury‐repair. Robust FGFR3 expression is restricted to the lower portion of the crypt where stem cells reside during normal intestinal development. Activation of the β‐catenin/Tcf‐4 complex is crucial for maintaining the intestinal stem cell compartment and for Paneth cell lineage allocation/differentiation. Previously we showed that FGFR3‐/‐ mice have fewer intestinal crypts, have a reduction in the total number of clonogenic stem cells, and decreased β‐catenin/Tcf‐4 activation. FGFR3‐/‐ mice at post‐natal days 14 and 21 display both a significant reduction in the number of intestinal Paneth cells and a reduction in mRNA levels of Paneth cell products. Since Paneth cell lineage allocation/differentiation is dependent upon β‐catenin/Tcf‐4 activation, we examined whether FGFR3 signaling can directly modulate Paneth cell specification. Caco2 cells treated with FGF9, a FGFR3 ligand, or co‐transfected with a constituitively active mutant (K650E) of FGFR3 had sustained β‐catenin/Tcf‐4 transcriptional activity. FGF9 increased mRNA levels of two Paneth cell markers, lysozyme and human defensin 5. These findings suggest that FGFR3 signaling can directly modulate Paneth cell specification possibly through the β‐catenin/Tcf‐4 signaling complex.