Background/Purpose We observed that fibroblast growth factor receptors 1 and 2 (Fgfr1, Fgfr2) are expressed during abdominal wall development in mice and hypothesized that conditional mutation of these genes would result in abdomial wall defects. Methods Section in situ hybridizations were performed for Fgfr1 and Fgfr2 on wild-type embryos at embryonic day (E) 11.5 and E13.5. Conditional mutation of Fgfr1 and Fgfr2 was achieved with a tamoxifen inducible Cre at E8.5. Litters were harvested at E17.5, whole mount photographs were taken, and paraffin sections were generated and stained with hematoxylin and eosin. Results Fgfr1 was expressed in ectoderm, lateral plate mesoderm, and myoblasts, whereas Fgfr2 was expressed almost exclusively in the early dermis and ectoderm of the abdominal wall. Conditional mutation of both Fgfr2 alleles and one Fgfr1 allele resulted in omphalocele in 38.7% of mutants. Histologic examination in mutants demonstrated disruptions in dermal and muscle development. Conclusions Mutant embryos with omphalocele arising from mutation in Fgfr1 and Fgfr2 exhibit disruptions in the development of the secondary abdominal wall structures. These findings are consistent with a model of ventral abdominal wall development in which organization of the muscles and connective tissue (secondary abdominal wall structures) is influenced by positional information emanating from the primary abdominal wall.

Background Homozygous null mutation of Fgfr2IIIb or its ligand Fgf10 results in duodenal atresia in mice. Mutations of either of these genes in humans cause Matthew-Wood syndrome and associated duodenal stenosis. Recently, mutations in the retinol-binding protein receptor gene STRA6 were reported to be implicated in this syndrome as well. This suggests that the retinoic acid (RA) signaling pathway interacts with the Fgf10-Fgfr2IIIb signaling pathway during duodenal development. Accordingly, we hypothesized that Fgfr2IIIb−/− mouse embryos would exhibit disruptions in expression of Raldh2, the gene for the enzyme that regulates the final step in the conversion of vitamin A to the active form RA, during duodenal atresia formation. Materials and Methods Fgfr2IIIb −/− mice were generated from heterozygous breedings. Embryos were harvested between embryonic day (E) 11.0 to E13.5 and genotyped by PCR. Duodenums were dissected out, fixed and photographed. Whole mount and section in situs were performed for Raldh2. Results Fgfr2IIIb−/− embryos demonstrate subtle changes in the duodenal morphology by E11.5 with complete involution of the atretic precursor by E13.5. Raldh2 appears to be down regulated as early at E11.5 in the atretic precursor a full 2 days before this segment disappears. Conclusions In Fgfr2IIIb−/− mouse embryos, a reduction of Raldh2 expression is observed within the region that is forming the atresia. This is the first demonstration of such an event in this model. As in humans, these results implicate disruptions between Fgfr2IIIb receptor function and RA signaling in the formation of this defect and indicate that Fgfr2IIIb−/− mouse embryos are a valid model for the study of the atretic spectrum of defects in human duodenal development.

No abstract