title: Inactivation of Sonic Hedgehog Signaling and Polydactyly in Limbs of Hereditary Multiple Malformation, a Novel Type ofTalpidMutant.
abstract: Hereditary Multiple Malformation (HMM) is a naturally occurring, autosomal recessive, homozygous lethal mutation found in Japanese quail. Homozygote embryos (hmm-/-) show polydactyly similar totalpid2andtalpid3mutants. Here we characterize the molecular profile of thehmm-/-limb bud and identify the cellular mechanisms that cause its polydactyly. Thehmm-/-limb bud shows a severe lack of sonic hedgehog (SHH) signaling, and the autopod has 4 to 11 unidentifiable digits with syn-, poly-, and brachydactyly. The Zone of Polarizing Activity (ZPA) of thehmm-/-limb bud does not show polarizing activity regardless of the presence of SHH protein, indicating that either the secretion pathway of SHH is defective or the SHH protein is dysfunctional. Furthermore, mesenchymal cells in thehmm-/-limb bud do not respond to ZPA transplanted from the normal limb bud, suggesting that signal transduction downstream of SHH is also defective. Since primary cilia are present in thehmm-/-limb bud, the causal gene must be different fromtalpid2andtalpid3. In thehmm-/-limb bud, a high amount of GLI3A protein is expressed and GLI3 protein is localized to the nucleus. Our results suggest that the regulatory mechanism of GLI3 is disorganized in thehmm-/-limb bud.
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University Nagoya, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Matsubara
authors.affiliation: Avian Bioscience Research Center, Graduate School of Bioagricultural Sciences, Nagoya University Nagoya, Japan.
authors.forename: Mikiharu
authors.initials: M
authors.lastname: Nakano
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University Nagoya, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Laboratory of Animal Breeding and Genetics, Graduate School of Biosphere Science, Hiroshima University Hiroshima, Japan.
authors.forename: Masaoki
authors.initials: M
authors.lastname: Tsudzuki
authors.affiliation: Institute of Development, Aging and Cancer, Tohoku University Sendai, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Funahashi
authors.affiliation: Department of Biophysics, Graduate School of Science, Kyoto University Kyoto, Japan.
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Agata
authors.affiliation: Avian Bioscience Research Center, Graduate School of Bioagricultural Sciences, Nagoya UniversityNagoya, Japan; Laboratory of Animal Genetics, Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya UniversityNagoya, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsuda
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University Nagoya, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuroiwa
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University Nagoya, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Suzuki
keywords: Hereditary Multiple Malformation; polydactyly; quail; sonic hedgehog