ArticleHuman molecular genetics2017
FGFR2 mutations in bent bone dysplasia syndrome activate nucleolar stress and perturb cell fate determination.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- Article
- Dynamic regulation and requirement for ribosomal RNA transcription during mammalian development.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- New developments in the biology of fibroblast growth factors.WIREs mechanisms of disease · 2022Review
- Nucleolin loss of function leads to aberrant Fibroblast Growth Factor signaling and craniofacial anomalies.Development (Cambridge, England) · 2022Article
- Pulling back the curtain: The hidden functions of receptor tyrosine kinases in development.Current topics in developmental biology · 2022Article
- FGF/FGFR signaling in health and disease.Signal transduction and targeted therapy · 2020Review
- Integrated Transcriptome and Network Analysis Reveals Spatiotemporal Dynamics of Calvarial Suturogenesis.Cell reports · 2020Article
- Fibroblast growth factors signaling in bone metastasis.Endocrine-related cancer · 2020Review
- Nuclear Fibroblast Growth Factor Receptor Signaling in Skeletal Development and Disease.Current osteoporosis reports · 2019Review
- Nuclear FGFR2 regulates musculoskeletal integration within the developing limb.Developmental dynamics : an official publication of the American Association of Anatomists · 2019Article
- tp53-dependent and independent signaling underlies the pathogenesis and possible prevention of Acrofacial Dysostosis-Cincinnati type.Human molecular genetics · 2018Article
- Fibroblast growth factor 2.Differentiation; research in biological diversityReview
Corrections and comments
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Authors and funding
5 authors at 1 institution in 2 countries.
Funding
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.
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