Abstract
Gain-of-function mutations in fibroblast growth factor (FGF) receptors result in chondrodysplasia and craniosynostosis syndromes, highlighting the critical role for FGF signaling in skeletal development. Although the FGFRs involved in skeletal development have been well characterized, only a single FGF ligand, FGF18, has been identified that regulates skeletal development during embryogenesis. Here we identify Fgf9 as a second FGF ligand that is critical for skeletal development. We show that Fgf9 is expressed in the proximity of developing skeletal elements and that Fgf9-deficient mice exhibit rhizomelia (a disproportionate shortening of proximal skeletal elements), which is a prominent feature of patients with FGFR3-induced chondrodysplasia syndromes. Although Fgf9 is expressed in the apical ectodermal ridge in the limb bud, we demonstrate that the Fgf9-/- limb phenotype results from loss of FGF9 functions after formation of the mesenchymal condensation. In developing stylopod elements, FGF9 promotes chondrocyte hypertrophy at early stages and regulates vascularization of the growth plate and osteogenesis at later stages of skeletal development.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Body Patterning
-
Bone Development / genetics
-
Bone Development / physiology*
-
Bone and Bones / blood supply
-
Bone and Bones / embryology
-
Cell Differentiation
-
Chondrocytes / cytology*
-
Chondrogenesis / genetics
-
Chondrogenesis / physiology*
-
Embryo Culture Techniques
-
Fibroblast Growth Factor 9 / deficiency
-
Fibroblast Growth Factor 9 / genetics
-
Fibroblast Growth Factor 9 / physiology*
-
Fibroblast Growth Factors / genetics
-
Fibroblast Growth Factors / physiology
-
Hedgehog Proteins / genetics
-
Hedgehog Proteins / metabolism
-
Humans
-
Mice
-
Mice, Knockout
-
Models, Biological
-
Osteogenesis / genetics
-
Osteogenesis / physiology
-
Parathyroid Hormone-Related Protein / genetics
-
Parathyroid Hormone-Related Protein / metabolism
-
Phenotype
-
Receptor, Fibroblast Growth Factor, Type 3 / deficiency
-
Receptor, Fibroblast Growth Factor, Type 3 / genetics
-
Signal Transduction
-
Vascular Endothelial Growth Factor A / genetics
-
Vascular Endothelial Growth Factor A / metabolism
Substances
-
Fgf9 protein, mouse
-
Fibroblast Growth Factor 9
-
Hedgehog Proteins
-
Parathyroid Hormone-Related Protein
-
Vascular Endothelial Growth Factor A
-
fibroblast growth factor 18
-
ihh protein, mouse
-
vascular endothelial growth factor A, mouse
-
Fibroblast Growth Factors
-
Fgfr3 protein, mouse
-
Receptor, Fibroblast Growth Factor, Type 3