FGFR2 mutations in bent bone dysplasia syndrome activate nucleolar stress and perturb cell fate determination.

Abstract

Fibroblast Growth Factor (FGF) signaling promotes self-renewal in progenitor cells by encouraging proliferation and inhibiting cellular senescence. Yet, these beneficial effects can be hijacked by disease-causing mutations in FGF receptor (FGFR) during embryogenesis. By studying dominant FGFR2 mutations that are germline in bent bone dysplasia syndrome (BBDS), we reveal a mechanistic connection between FGFR2, ribosome biogenesis, and cellular stress that links cell fate determination to disease pathology. We previously showed that FGFR2 mutations in BBDS, which amplify nucleolar targeting of FGFR2, activate ribosomal DNA (rDNA) transcription and delay differentiation in osteoprogenitor cells and patient-derived bone. Here we find that the BBDS mutations augment the ability of FGFR2 to recruit histone-remodeling factors that epigenetically activate transcriptionally silent rDNA. Nucleolar morphology is controlled by chromatin structure, and the high levels of euchromatic rDNA induced by the BBDS mutations direct nucleolar disorganization, alter ribosome biogenesis, and activate the Rpl11-Mdm2-p53 nucleolar stress response pathway. Inhibition of p53 in cells expressing the FGFR2 mutations in BBDS rescues delayed osteoblast differentiation, suggesting that p53 activation is an essential pathogenic factor in, and potential therapeutic target for, BBDS. This work establishes rDNA as developmentally regulated loci that receive direct input from FGF signaling to balance self-renewal and cell fate determination.