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

Area of Science:

• Molecular Biology
• Developmental Biology
• Genetics

Background:

• Fibroblast Growth Factor (FGF) signaling is crucial for progenitor cell self-renewal, proliferation, and senescence inhibition.
• Mutations in FGF receptors (FGFRs) can disrupt normal development, leading to diseases like bent bone dysplasia syndrome (BBDS).

Purpose of the Study:

• To investigate the mechanistic link between FGFR2 mutations in BBDS, ribosome biogenesis, and cellular stress.
• To understand how these mutations affect cell fate determination and disease pathology.

Main Methods:

• Studied dominant FGFR2 mutations associated with BBDS.
• Analyzed nucleolar targeting of FGFR2, ribosomal DNA (rDNA) transcription, and histone-remodeling factor recruitment.
• Investigated nucleolar morphology, ribosome biogenesis, and the Rpl11-Mdm2-p53 pathway.
• Assessed the effect of p53 inhibition on osteoblast differentiation.

Main Results:

• BBDS-associated FGFR2 mutations amplify nucleolar targeting, activating rDNA transcription and delaying osteoprogenitor cell differentiation.
• Mutant FGFR2 recruits histone-remodeling factors, epigenetically activating silent rDNA, leading to nucleolar disorganization and altered ribosome biogenesis.
• The Rpl11-Mdm2-p53 nucleolar stress response pathway is activated by these mutations.

Conclusions:

• FGFR2 mutations in BBDS disrupt ribosome biogenesis via epigenetic rDNA activation and nucleolar stress, impacting cell fate.
• p53 activation is a key pathogenic factor in BBDS, representing a potential therapeutic target.
• Ribosomal DNA is a developmentally regulated locus directly influenced by FGF signaling to balance self-renewal and cell fate.