Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice

Honghao Zhang, Nobuhiro Kamiya, Takehito Tsuji, Haruko Takeda, Greg Scott, Sudha Rajderkar, Manas K. Ray, Yoshiyuki Mochida, Benjamin Allen, Veronique Lefebvre, Irene H. Hung, David M. Ornitz, Tetsuo Kunieda, Yuji Mishina

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article numbere1006510
JournalPLoS Genetics
Volume12
Issue number12
DOIs
Publication statusPublished - Dec 1 2016

Fingerprint

Dwarfism
fibroblast growth factors
Fibroblast Growth Factors
Erinaceidae
dwarfing
Ellis-Van Creveld Syndrome
limb
pathogenesis
Extremities
mutants
Hedgehogs
mice
inactivation
growth plate
organogenesis
tissue culture
teeth
cell culture
Tooth Abnormalities
alleles

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice. / Zhang, Honghao; Kamiya, Nobuhiro; Tsuji, Takehito; Takeda, Haruko; Scott, Greg; Rajderkar, Sudha; Ray, Manas K.; Mochida, Yoshiyuki; Allen, Benjamin; Lefebvre, Veronique; Hung, Irene H.; Ornitz, David M.; Kunieda, Tetsuo; Mishina, Yuji.

In: PLoS Genetics, Vol. 12, No. 12, e1006510, 01.12.2016.

Research output: Contribution to journalArticle

Zhang, H, Kamiya, N, Tsuji, T, Takeda, H, Scott, G, Rajderkar, S, Ray, MK, Mochida, Y, Allen, B, Lefebvre, V, Hung, IH, Ornitz, DM, Kunieda, T & Mishina, Y 2016, 'Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice', PLoS Genetics, vol. 12, no. 12, e1006510. https://doi.org/10.1371/journal.pgen.1006510
Zhang, Honghao ; Kamiya, Nobuhiro ; Tsuji, Takehito ; Takeda, Haruko ; Scott, Greg ; Rajderkar, Sudha ; Ray, Manas K. ; Mochida, Yoshiyuki ; Allen, Benjamin ; Lefebvre, Veronique ; Hung, Irene H. ; Ornitz, David M. ; Kunieda, Tetsuo ; Mishina, Yuji. / Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice. In: PLoS Genetics. 2016 ; Vol. 12, No. 12.
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