Fibroblast growth factor receptor‐3 is expressed in undifferentiated intestinal epithelial cells during murine crypt morphogenesis

Abstract

Prior studies have demonstrated that fibroblast growth factor receptor-3 (FGFR-3) regulates proliferation of undifferentiated intestinal epithelial cells in vitro. However, the function(s) of FGFR-3-mediated signaling during intestinal development and epithelial differentiation in vivo remain unknown. The goal of this study was to define the temporal, regional, and cell-specific patterns of FGFR-3 expression and its ligands during normal intestinal ontogeny and epithelial regeneration. Both the IIIb and IIIc isoforms of FGFR-3 mRNA, which result from differential splicing of the FGFR-3 primary transcript, were detected in mouse small intestine as early as embryonic day 16. FGFR-3 levels peaked in the small intestine from 7 to 21 days after birth and decreased thereafter to reach the low levels observed in adult mice. FGFR-3 IIIb and IIIc mRNA levels were highest in the duodenum and proximal jejunum with lower levels of both seen in the distal jejunum, ileum, and colon. FGFR-3 was expressed in a subset of proliferating undifferentiated crypt epithelial cells located in the intervillous epithelium and in the lower half of nascently forming crypts but not in differentiated epithelial cell types. FGFR-3 IIIb was the dominant isoform expressed in both small intestinal and colonic crypts. Expression of FGF1, FGF2, and FGF9, known ligands of FGFR-3, paralleled patterns of FGFR-3 expression during gut development. These data suggest that signaling through FGFR-3 plays a role in regulating morphogenic events involved in formation of intestinal crypts and/or the fate of epithelial stem cells.

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

“…Our previous findings that FGFR-3 and its cognate ligands FGF1, FGF2, and FGF9 are coordinately expressed at high levels during postnatal intestinal development suggested that this signaling pathway mediates the morphogenic events at this time (50). Although our prior study did not define the specific role(s) of FGFR-3 in regulating developmental events in the intestine, the observation that expression of FGFR-3 was restricted to undifferentiated epithelial cells within the lower portion of the crypt, a region known to house the epithelial stem cell population, further suggested that signaling through FGFR-3 is important in mediating some aspect of epithelial morphogenesis.…”

“…Our studies focused on the consequence of FGFR-3 deletion during stem cell proliferation and crypt morphogenesis, dynamic processes that take place during postnatal intestinal development. Arnaud-Dabernat and colleagues examined the consequences of FGFR-3 deletion on the replication of transit amplifying cells in the unperturbed adult intestine, a developmental stage at which expression of FGFR-3 in crypt epithelial cells is low, the number of crypts is static, and crypt stem cells are relatively quiescent compared with the suckling mouse intestine (50). It is possible that the response of the transit amplifying cell population of the adult intestine to FGFR-3 signaling is different from that of stem cells of the developing intestine.…”

“…In wild-type mice, FGFR-3 is highly expressed on the surface of a subset of epithelial cells in the lower half of crypts present in the suckling mouse intestine (50). In contrast, immunoreactive FGFR-3 was not seen in epithelial cells of mice homozygous for a targeted disruption of the FGFR-3 gene, i.e., FGFR-3 Ϫ/Ϫ mice ( Fig.…”

“…Ϫ/Ϫ mice form normal numbers of intestinal crypts, since the number of crypts increases markedly in the suckling mouse intestine and FGFR-3 is highly expressed in the developing intestine during this time period (50). To determine whether FGFR-3 signaling regulates crypt formation, we quantified the number of small intestinal crypts in FGFR-3 Ϫ/Ϫ and wild-type mice at various developmental time points.…”

“…We recently found that one of the receptors for this important family of growth factors, FGFR-3, is highly expressed by undifferentiated crypt epithelial cells in the developing intestine. Additionally, potential ligands for this receptor are highly expressed during crypt morphogenesis in the suckling mouse intestine (50). These findings led us to ask whether FGFR-3-mediated signaling plays a critical role in regulating morphogenic events and/or functional differentiation of crypt epithelial cells during intestinal development (50).…”