title: Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice.
abstract: Ellis-van Creveld (EvC) syndrome is a skeletal dysplasia, characterized by short limbs, postaxial polydactyly, and dental abnormalities. EvC syndrome is also categorized as a ciliopathy because of ciliary localization of proteins encoded by the two causative genes, EVC and EVC2 (aka LIMBIN). While recent studies demonstrated important roles for EVC/EVC2 in Hedgehog signaling, there is still little known about the pathophysiological mechanisms underlying the skeletal dysplasia features of EvC patients, and in particular why limb development is affected, but not other aspects of organogenesis that also require Hedgehog signaling. In this report, we comprehensively analyze limb skeletogenesis in Evc2 mutant mice and in cell and tissue cultures derived from these mice. Both in vivo and in vitro data demonstrate elevated Fibroblast Growth Factor (FGF) signaling in Evc2 mutant growth plates, in addition to compromised but not abrogated Hedgehog-PTHrP feedback loop. Elevation of FGF signaling, mainly due to increased Fgf18 expression upon inactivation of Evc2 in the perichondrium, critically contributes to the pathogenesis of limb dwarfism. The limb dwarfism phenotype is partially rescued by inactivation of one allele of Fgf18 in the Evc2 mutant mice. Taken together, our data uncover a novel pathogenic mechanism to understand limb dwarfism in patients with Ellis-van Creveld syndrome.
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Michigan, United States of America.
authors.forename: Honghao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Michigan, United States of America.|Reproductive and Developmental Biology Laboratory (RDBL), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina, United States of America.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kamiya
authors.affiliation: Graduate School of Environmental and Life Science, Okayama University, Okayama City, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: Reproductive and Developmental Biology Laboratory (RDBL), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina, United States of America.
authors.forename: Haruko
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Knock Out Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina, United States of America.
authors.forename: Greg
authors.initials: G
authors.lastname: Scott
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Michigan, United States of America.
authors.forename: Sudha
authors.identifier: http://orcid.org/0000-0003-2001-3450
authors.initials: S
authors.lastname: Rajderkar
authors.affiliation: Knock Out Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina, United States of America.
authors.forename: Manas K
authors.initials: MK
authors.lastname: Ray
authors.affiliation: Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, Boston, Massachusetts, United States of America.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mochida
authors.affiliation: School of Medicine, University of Michigan, Michigan, United States of America.
authors.forename: Benjamin
authors.identifier: http://orcid.org/0000-0003-2323-8313
authors.initials: B
authors.lastname: Allen
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, United States of America.
authors.forename: Veronique
authors.initials: V
authors.lastname: Lefebvre
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.|Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Irene H
authors.initials: IH
authors.lastname: Hung
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: David M
authors.identifier: http://orcid.org/0000-0003-1592-7629
authors.initials: DM
authors.lastname: Ornitz
authors.affiliation: Graduate School of Environmental and Life Science, Okayama University, Okayama City, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kunieda
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Michigan, United States of America.|Reproductive and Developmental Biology Laboratory (RDBL), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina, United States of America.|Knock Out Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina, United States of America.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004392:Dwarfism / Q000235:genetics* / Q000473:pathology; D004613:Ellis-Van Creveld Syndrome / Q000235:genetics* / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D006132:Growth Plate / Q000254:growth & development / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D050505:Mutant Proteins / Q000096:biosynthesis / Q000235:genetics; D017689:Polydactyly / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D014071:Tooth Abnormalities / Q000235:genetics / Q000473:pathology
chemical_list: C541939:EVC2 protein, mouse; C523527:Evc protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D050505:Mutant Proteins; C113569:fibroblast growth factor 18; D005346:Fibroblast Growth Factors