title: Bent bone dysplasia syndrome reveals nucleolar activity for FGFR2 in ribosomal DNA transcription.
abstract: Fibroblast growth factor receptor 2 (FGFR2) promotes osteoprogenitor proliferation and differentiation during bone development, yet how the receptor elicits these distinct cellular responses remains unclear. Analysis of the FGFR2-skeletal disorder bent bone dysplasia syndrome (BBDS) demonstrates that FGFR2, in addition to its canonical signaling activities at the plasma membrane, regulates bone formation from within the nucleolus. Previously, we showed that the unique FGFR2 mutations that cause BBDS reduce receptor levels at the plasma membrane and diminish responsiveness to extracellular FGF2. In this study, we find that these mutations, despite reducing canonical signaling, enhance nucleolar occupancy of FGFR2 at the ribosomal DNA (rDNA) promoter. Nucleolar FGFR2 activates rDNA transcription via interactions with FGF2 and UBF1 by de-repressing RUNX2. An increase in the nucleolar activity of FGFR2 in BBDS elevates levels of ribosomal RNA in the developing bone, consequently promoting osteoprogenitor cell proliferation and decreasing differentiation. Identifying FGFR2 as a transcriptional regulator of rDNA in bone unexpectedly reveals a nucleolar route for FGF signaling that allows for independent regulation of osteoprogenitor cell proliferation and differentiation.
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry and Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Neben
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry and.
authors.forename: Brian
authors.initials: B
authors.lastname: Idoni
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry and Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Salva
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Creighton T
authors.initials: CT
authors.lastname: Tuzon
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Judd C
authors.initials: JC
authors.lastname: Rice
authors.affiliation: Departments of Orthopaedic Surgery, Human Genetics, Pediatrics and Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry and Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA, amerrill@usc.edu.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Merrill
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D004275:DNA, Ribosomal / Q000235:genetics*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid; D014158:Transcription, Genetic
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D004275:DNA, Ribosomal; D035463:Pol1 Transcription Initiation Complex Proteins; C063844:transcription factor UBF; D016222:Fibroblast Growth Factor 2; D051497:Receptor, Fibroblast Growth Factor, Type 2