title: A combined series of Fgf9 and Fgf18 mutant alleles identifies unique and redundant roles in skeletal development.
abstract: Fibroblast growth factor (FGF) signaling is a critical regulator of skeletal development. Fgf9 and Fgf18 are the only FGF ligands with identified functions in embryonic bone growth. Mice lacking Fgf9 or Fgf18 have distinct skeletal phenotypes; however, the extent of overlapping or redundant functions for these ligands and the stage-specific contributions of FGF signaling to chondrogenesis and osteogenesis are not known. To identify separate versus shared roles for FGF9 and FGF18, we generated a combined series of Fgf9 and Fgf18 null alleles. Analysis of embryos lacking alleles of Fgf9 and Fgf18 shows that both encoded ligands function redundantly to control all stages of skeletogenesis; however, they have variable potencies along the proximodistal limb axis, suggesting gradients of activity during formation of the appendicular skeleton. Congenital absence of both Fgf9 and Fgf18 results in a striking osteochondrodysplasia and revealed functions for FGF signaling in early proximal limb chondrogenesis. Additional defects were also noted in craniofacial bones, vertebrae, and ribs. Loss of alleles of Fgf9 and Fgf18 also affect the expression of genes encoding other key intrinsic skeletal regulators, including IHH, PTHLH (PTHrP), and RUNX2, revealing potential direct, indirect, and compensatory mechanisms to coordinate chondrogenesis and osteogenesis.
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84132, United States; Cancer and Developmental Biology Lab, National Cancer Institute, Frederick, MD 21701, United States; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States. Electronic address: irene.hung@hsc.utah.edu.
authors.forename: Irene H
authors.initials: IH
authors.lastname: Hung
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84132, United States.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Schoenwolf
authors.affiliation: Cancer and Developmental Biology Lab, National Cancer Institute, Frederick, MD 21701, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Lewandoski
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States. Electronic address: dornitz@wustl.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics*; D001842:Bone and Bones / Q000002:abnormalities / Q000196:embryology*; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism; D020219:Chondrogenesis / Q000235:genetics*; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis; D051525:Fibroblast Growth Factor 9 / Q000235:genetics / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology*; D006132:Growth Plate / Q000196:embryology; D053823:Hedgehog Proteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D010009:Osteochondrodysplasias / Q000235:genetics*; D010012:Osteogenesis / Q000235:genetics*; D044162:Parathyroid Hormone-Related Protein / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C496460:Fgf9 protein, mouse; D051525:Fibroblast Growth Factor 9; D053823:Hedgehog Proteins; D044162:Parathyroid Hormone-Related Protein; C493716:Runx2 protein, mouse; C113569:fibroblast growth factor 18; C514061:ihh protein, mouse; D005346:Fibroblast Growth Factors
keywords: Chondrogenesis; FGF; Growth plate; Mouse