Skeletal anomalies affect a significant proportion of the population, with an incidence rate of 1 case per 3000 births. Numerous skeletal birth defects arise as a consequence of mutations in genes that define when and where skeletal progenitor cells transition from a self-renewing state to one of terminal differentiation during development. Fibroblast Growth Factor Receptor 2 (FGFR2) is one such gene whose mutations are responsible for at least 10 distinct disorders that exhibit abnormalities within the craniofacial ad limb skeleton. FGFR2 acts as a key signaling node in bone by regulating the binary choice of osteoprogenitor cells to either self-renew or to differentiate. However, the mechanism by which FGFR2 controls these distinct cellular outcomes is not completely understood. The overall objective of this proposal is to understand with much greater specificity how FGFR2 regulates skeletal development by revealing the mechanism through which nuclear FGFR2 regulates ribosome biogenesis. The abundance of ribosomes regulates a cell's capacity for protein synthesis; heterogeneities in the composition of ribosomes regulate specificity in translation. Translation of mRNA into protein is the true endpoint of gene expression and because there is a discrepancy between mRNA and protein levels for many key regulatory genes, controlling translation through ribosome biogenesis is critical in regulating cell growth, proliferation, and differentiation. There is strong evidence for such control in the developing skeleton where decreased ribosome biogenesis is implicated in the pathogenesis of skeletal anomalies. We have uncovered compelling evidence that the FGFR2-disorder Bent Bone Dysplasia Syndrome (BBDS) is cause by increased ribosome biogenesis. We found that the mutations in BBDS enhance a normal activity for FGFR2 in the nucleolus where it activates rDNA transcription, the rate-limiting step in building ribosomes. FGFR2-mediated increase in rDNA transcription elevates the number of ribosomes and is coincident with an upsurge in proliferation at the expense of differentiation in osteoprogenitor cells. This proposal will test the hypothesis that nuclear FGFR2 regulates skeletal progenitor cell development by modulating protein synthesis via ribosome biogenesis.
In Aim 1, we will distinguish the precise roles of nuclear and membrane FGFR2 signaling during bone formation.
In Aim 2, we will define how nuclear FGFR2 regulates ribosome synthesis in skeletal progenitor cells.
In Aim 3, we will determine the extent to which increased rRNA regulates development of skeletal progenitor cells by modulating the identity and amount of proteins produced. This contribution will have significant and broad impact because it will 1) fundamentally advance our understanding of the mechanisms underpinning diseases caused by FGFR2 and ribosome dysfunction, including birth defects and cancer, and 2) create new opportunities for therapeutic strategies that target nuclear FGFR2 and intrinsically correct aberrant cell proliferation and differentiation in these diseases.

Public Health Relevance

Numerous skeletal birth defects arise as a consequence of mutations in genes that define when and where skeletal progenitor cells form bone during development. Mutations in Fibroblast Growth Factor Receptor 2 (FGFR2) are responsible for at least 10 distinct skeletal birth defects and thus advancing our fundamental understanding of how FGFR2 regulates skeletal progenitor cells will identify new targets for therapeutic intervention. Towards this goal, we will study an unexpected role for FGFR2 in protein synthesis using the unique FGFR2 mutations that we identified in patients with Bent Bone Dysplasia Syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE025222-03
Application #
9304184
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Wan, Jason
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Southern California
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
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