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Bent Bone Dysplasia Syndrome defines a nuclear role for FGFR2 in skeletal development
Author(s) -
Merrill Amy Elizabeth,
Idoni Brian,
Neben Cynthia,
Salva Joanna,
Roberts Ryan,
Krakow Deborah
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.319.2
Subject(s) - microbiology and biotechnology , ribosome biogenesis , biology , fibroblast growth factor , fibroblast growth factor receptor 2 , cancer research , receptor , genetics , rna , ribosome , gene
Development of the skeleton requires dynamic regulation of osteoprogenitor cell renewal and commitment. These processes are dually promoted by Fibroblast Growth Factor Receptor 2 ( FGFR2 ), as evidenced by congenital disorders resulting from FGFR2 mutations. However, how FGFR2 activity balances proliferation and differentiation is unclear. We have identified unique FGFR2 mutations in Bent Bone Dysplasia Syndrome (BBDS), a disorder deficient in osteoblasts despite abundant osteoprogenitor cells. This phenotype of enhanced proliferation and reduced differentiation suggests these FGFR2 mutations uncouple distinct receptor activities in osteoprogenitor cells. The FGFR2 mutations in BBDS reside in the transmembrane domain, prevent receptor incorporation into the plasma membrane, and consequently reduce receptor responsiveness to secreted FGFs. Despite decreased canonical FGF signaling, mutant FGFR2 enhances a noncanonical nuclear function for FGFR2: we found that FGFR2 acts in the nucleolus where it associates with FGF2 and UBF1 to promote ribosomal DNA transcription. This nucleolar association is enriched by mutant FGFR2 and consequently elevates ribosomal RNA levels in the bones of BBDS patients. Delineation of BBDS reveals that nuclear FGFR2 signaling balances osteoprogenitor cell renewal and commitment by regulating ribosome biogenesis. Grant Funding Source : March of Dimes 5‐FY12–166, NIH/NIDCR 5 P30 DE020750 ‐02