Fibroblast Growth Factor Receptor-3 (FGFR-3) Regulates Expression of Paneth Cell Lineage-specific Genes in Intestinal Epithelial Cells through both TCF4/β-Catenin-dependent and -independent Signaling Pathways

Abstract

Fibroblast growth factor receptor-3 (FGFR-3Despite the critical importance of Paneth cells in maintaining gut homeostasis, knowledge of the pathways regulating Paneth cell differentiation and function has only recently begun to emerge. Studies using transgenic mice or mice with targeted mutations in epithelial regulatory genes, including components of the Wnt signaling pathway (Tcf4, Fz5, Sox9, and Apc), FGFR-3, and PPAR␤/␦, have identified these genes as key regulators of Paneth cell differentiation and expression of defensin peptides in vivo (9 -14). However, the lack of an adequate intestinal epithelial cell culture system that can recapitulate features of Paneth cell differentiation and maturation has hampered direct investigation of how these signaling pathways may interact in regulating Paneth cell differentiation and functional maturation.We recently reported that signaling through FGFR-3 in crypt epithelial cells regulates both the number of epithelial stem cells and Paneth cell differentiation during postnatal gut development (13,15). FGFR-3 is highly expressed along the membranes of cells in the lower portion of the crypt in the developing mouse intestine (15). FGFRs are members of the receptor-tyrosine kinase family. Ligand binding induces dimerization, autophosphorylation, and initiation of a signal transduction cascade that ultimately results in modification of gene expression. Ligands for FGFR-3, FGF1, FGF2, and FGF9, are up-regulated in the postnatal murine small intestine from birth through the suckling weaning transition, when crypt mor-

Paneth cells expand from newly created and preexisting cells during repair after doxorubicin-induced damage

“…Furthermore, signaling through FGFR3 in Paneth cells activates ␤-catenin/Tcf4-dependent and -independent mechanisms necessary for Paneth cell maturation (7). After Dox-induced damage, we found significant increases in the FGFR3 ligands FGF-9 and FGF-18, suggesting that expansion of Paneth/ intermediate cells may involve FGFR3 signaling.…”

“…Recent evidence also suggests that signaling through FGFR3 plays a critical role in Paneth cell maturation (7,40). Furthermore, signaling through FGFR3 in Paneth cells activates ␤-catenin/Tcf4-dependent and -independent mechanisms necessary for Paneth cell maturation (7).…”

“…The mechanism(s) that drive(s) Paneth cell expansion after Dox-induced injury is unclear. Numerous trophic factors, including Wnts, FGFs, serotonin, Indian hegdehog (Ihh), and colony-stimulating factor, are known to influence the number of Paneth cells residing at the base of intestinal crypts (7,11,16,34,37). However, little is known about the mechanisms by which damage to intestinal epithelium influences Paneth cell numbers or their differentiation.…”

Studies on the Interaction of Tumor-Derived HD5 Alpha Defensins with Adenoviruses and Implications for Oncolytic Adenovirus Therapy

“…An indirect line of support for the association of HD5 and cancer comes from the fact that FGF9 signaling through FGFR-3 triggers HD5 expression (16). FGF9 is a target of the Wnt/␤-catenin pathway.…”

“…Two studies report that HD5 peptide is present in colon cancer and most likely produced by malignant Paneth cells (14,15). HD5 expression was also documented in the colon cancer cell line Caco-2 where HD5 gene expression can be increased by recombinant fibroblast growth factor 9 (FGF9) (16). Because HD5 is found in other epithelial tissues, it is thought that it is produced by epithelial cancers other than colon cancer (5).…”