title: Generation of Evc2/Limbin global and conditional KO mice and its roles during mineralized tissue formation.
abstract: Ellis-van Creveld (EvC) syndrome (OMIM 225500) is an autosomal recessive disease characterized with chondrodysplastic dwarfism in association with abnormalities in oral cavity. Ciliary proteins EVC and EVC2 have been identified as causative genes and they play an important role on Hedgehog signal transduction. We have also identified a causative gene LIMBIN for bovine chondrodysplastic dwarfism (bcd) that is later identified as the bovine ortholog of EVC2. Here, we report generation of conventional and conditional mutant Evc2/Limbin alleles that mimics mutations found in EvC patients and bcd cattle. Resulted homozygous mice showed no ciliary localization of EVC2 and EVC and displayed reduced Hedgehog signaling activity in association with skeletal and oral defects similar to the EvC patients. Cartilage-specific disruption of Evc2/Limbin resulted in similar but milder skeletal defects, whereas osteoblast-specific disruption did not cause overt changes in skeletal system. Neural crest-specific disruption of Evc2/Limbin resulted in defective incisor growth similar to that seen in conventional knockouts; however, differentiation of amelobolasts was relatively normal in the conditional knockouts. These results showcased functions of EVC2/LIMBIN during formation of mineralized tissues. Availability of the conditional allele for this gene should facilitate further detailed analyses of the role of EVC2/LIMBIN in pathogenesis of EvC syndrome. genesis 53:612-626, 2015. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Michigan.
authors.forename: Honghao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.|Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège, 1 Avenue De L'hôpital, Liège, Belgium.
authors.forename: Haruko
authors.initials: H
authors.lastname: Takeda
authors.affiliation: The Graduate School of Environment and Life Science, Okayama University, Okayama City, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Michigan.|Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.|Faculty of Budo and Sport Studies, Tenri University, Nara, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kamiya
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Michigan.
authors.forename: Sudha
authors.initials: S
authors.lastname: Rajderkar
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Michigan.
authors.forename: Ke'Ale
authors.initials: K
authors.lastname: Louie
authors.affiliation: College of Literature, Science and the Arts, University of Michigan, Michigan.
authors.forename: Crystal
authors.initials: C
authors.lastname: Collier
authors.affiliation: Knock out Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
authors.forename: Greg
authors.initials: G
authors.lastname: Scott
authors.affiliation: Knock out Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
authors.forename: Manas
authors.initials: M
authors.lastname: Ray
authors.affiliation: Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, 700 Albany Street, Boston, Massachusetts.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mochida
authors.affiliation: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Michigan.
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
authors.affiliation: The Graduate School of Environment 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.|Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.|Knock out Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
keywords: Evc2; Limbin; mouse; primary cilium