An unexpected nucleolar role for FGFR2 in development and disease (213.4)

Abstract

Numerous skeletal birth defects arise from mutations in genes that regulate when and where osteoprogenitor cells transition from a proliferative state to one of terminal differentiation during development. Fibroblast Growth Factor Receptor 2 (FGFR2), whose mutations cause 10 distinct skeletal disorders, is one such regulator. While FGFR2 promotes both proliferation and differentiation in osteoprogenitor cells, how the receptor executes and links these opposed activities remains unclear. Our analysis of Bent Bone Dysplasia Syndrome (BBDS), a FGFR2‐disorder with excess osteoprogenitor cells and insufficient osteoblasts, has identified a nucleolar role for FGFR2 that can resolve this paradox. The unique FGFR2 mutations in BBDS enhance receptor localization to the nucleolus where it interacts with UBF1 at the ribosomal RNA promoter to activate transcription by repressing Runx2. Transcription of rRNA is the rate‐limiting step in producing ribosomes, which are the protein producing machines in all cells. A cell’s proliferative potential relies on protein synthesis and thus during differentiation lineage specific transcription factors, such as Runx2, arrest progenitor cell proliferation by inhibiting rRNA transcription. That nucleolar FGFR2 regulates transcription of Runx2 target genes suggests a novel mechanism through which the receptor links osteoprogenitor proliferation to differentiation.