A genetic mechanism for cecal atresia: the role of the Fgf10 signaling pathway.

BACKGROUND: Intestinal atresia represents a significant surgically correctable cause of intestinal obstruction in neonates. Intestinal development proceeds as a tube-like structure with differentiation along its axis. As the intestine differentiates, the cecum develops at the transition from small to large intestine. Fgf10 is known to serve a key role in budding morphogenesis; however, little is known about its role in the development of this transitional structure. Here we evaluate the effect of Fgf10/Fgfr2b invalidation on the developing cecum. MATERIALS AND METHODS: Wild-type C57Bl/6, Fgf10(-/-), and Fgfr2b(-/-) embryos harvested from timed pregnant mothers were analyzed for cecal phenotype, Fgf10 expression, and differentiation of smooth muscle actin. RESULTS: Wt cecal development is first evident at E11.5. FGF10 is discreetly expressed in the area of the developing cecum at early stages of development. One hundred percent of Fgf10(-/-) and Fgfr2b(-/-) mutant embryos demonstrate cecal atresia with absence of epithelial and muscular layers. The development of neighboring anatomical structures such as the ileocecal valve is not affected by Fgf10/Fgfr2b invalidation. CONCLUSIONS: FGF10 expression is localized to the cecum early in the normal development of the cecum. Fgf10(-/-) and Fgfr2b(-/-) mutant embryos demonstrate cecal atresia with complete penetrance. Epithelial and muscular layers of the cecum are not present in the atretic cecum. The Fgf10(-/-) and Fgfr2b(-/-) mutants represent a genetically reproducible animal model of autosomal recessive intestinal atresia.

Requirement for fibroblast growth factor 10 or fibroblast growth factor receptor 2-IIIb signaling for cecal development in mouse.

Epithelial-mesenchymal interactions are critical for the formation of gastrointestinal buds such as the cecum from the midgut, but the mechanisms regulating this process remain unclear. To investigate this problem, we have studied the temporal and spatial expression of key genes known to orchestrate branching morphogenesis. At E10.5, Fibroblast growth factor 10 (Fgf10) is specifically expressed in the mesenchyme above the future cecal epithelial bud, whereas Fgfr2b is found throughout the gut epithelium. From E11.5 onwards, Fgf10 expression is found throughout the cecum mesenchyme. Other relevant signaling molecules such as Sonic hedgehog, Wnt2b, and Tbx4 transcripts are found throughout the gut epithelium, including the cecum. Epithelial expression is also seen for Sprouty2, but only from E14.5 onwards. By contrast, Bone morphogenetic 4 (Bmp4) and Pitx2 are specifically expressed in the mesenchyme of the cecal bud at E11.5. Abrogation of either Fgf10 or Fgfr2b leads to similar phenotypes characterized by an arrest of epithelial invasion into the cecal mesenchymal tissue. However, a bud of undifferentiated cecal mesenchymal tissue is maintained throughout development. Our results further indicate that mesenchymal FGF10 acts mostly through the epithelial FGFR2b receptor; thereby triggering invasion of the midgut epithelium into the adjacent mesenchyme via an increased rate of epithelial proliferation at the tip of the cecum. Thus, FGF10 signaling via FGFR2b appears to be critical in the extension of the epithelium into the mesenchyme during cecal development.