A nucleolar role for FGFR2 in bent bone dysplasia syndrome (344.5)

Abstract

Fibroblast Growth Factor Receptor 2 (FGFR2) promotes osteoprogenitor cell proliferation and differentiation during bone development, yet it remains unclear how the receptor couples these distinct cellular processes. Analysis of the new FGFR2‐skeletal disorder Bent Bone Dysplasia Syndrome (BBDS) suggests that the receptor, in addition to its canonical activities, regulates bone formation within the nucleolus. We previously showed that the FGFR2 mutations in BBDS reduce receptor levels at the plasma membrane and markedly diminish responsiveness to extracellular FGF2. Despite decreased canonical FGF signaling, cells with mutant FGFR2 show enhanced nucleolar localization with intracellular FGF2. The nucleolus is the site of ribosome biogenesis, and ribosome dysfunction is linked to skeletal birth defects. By employing the BBDS mutations in cultured preosteoblasts, we found that nucleolar FGFR2, along with FGF2 and the rDNA transcription factor UBF1, interacts at the rDNA promoter to promote transcription and subsequently cell proliferation. Our studies also show that nucleolar FGFR2 blocks the transcriptional repressor activities of RUNX2, the master regulator of osteoblast differentiation, at rDNA. Together this data suggest that nucleolar FGFR2 links proliferation and differentiation in preosteoblasts by regulating rRNA transcription, the rate‐limiting step in ribosome production.Grant Funding Source: Supported by NIH/NIDCR #T90DE021982 to C.L.N., MOD #5‐FY12‐166 to A.E.M., NIDCR 5 P30 DE020750‐02