A noncanonical nuclear role for fibroblast growth factor signaling in skeletal development (921.6)

Abstract

Fibroblast Growth Factor (FGF) signaling plays crucial roles in osteochondral progenitor cell proliferation and differentiation as seen by the multiple skeletal dysplasias resulting from abnormal FGF signaling. We identified that the skeletal dysplasia Bent Bone Dysplasia Syndrome (BBDS) results from unique FGF Receptor 2 (FGFR2) mutations that reduce canonical membrane signaling, while also enhancing a noncanonical nuclear role for the receptor in ribosome biogenesis. To determine how canonical and noncanonical FGFR2 signaling individually contribute to skeletal development and the pathogenesis of BBDS, we blocked membrane FGFR2 signaling with a chemical inhibitor and enhanced nuclear FGFR2 signaling by employing the BBDS mutations. In a bone organ culture assay, avian mandibles grown with inhibitors of membrane FGF signaling displayed reduced bone formation and exhibited uncharacteristic hypertrophy of Meckel’s cartilage. Expression of the BBDS FGFR2 mutations in developing chicken embryos caused increased proliferation and abnormal patterning in bone and cartilage. These results suggest that membrane FGF signaling is important in osteochondral progenitor differentiation and maturation while nuclear FGF signaling regulates proliferation. Combined our research shows that canonical and noncanonical FGF signaling have distinct roles during skeletal development.Grant Funding Source: Supported by NIH#5T32HD060549‐02 to JES, MOD #5‐FY12‐166 to AEM, NIH #5P30DE020750‐02