title: The brain-specific RasGEF very-KIND is required for normal dendritic growth in cerebellar granule cells and proper motor coordination.
abstract: Very-KIND/Kndc1/KIAA1768 (v-KIND) is a brain-specific Ras guanine nucleotide exchange factor carrying two sets of the kinase non-catalytic C-lobe domain (KIND), and is predominantly expressed in cerebellar granule cells. Here, we report the impact of v-KIND deficiency on dendritic and synaptic growth in cerebellar granule cells in v-KIND knockout (KO) mice. Furthermore, we evaluate motor function in these animals. The gross anatomy of the cerebellum, including the cerebellar lobules, layered cerebellar cortex and densely-packed granule cell layer, in KO mice appeared normal, and was similar to wild-type (WT) mice. However, KO mice displayed an overgrowth of cerebellar granule cell dendrites, compared with WT mice, resulting in an increased number of dendrites, dendritic branches and terminals. Immunoreactivity for vGluT2 (a marker for excitatory presynapses of mossy fiber terminals) was increased in the cerebellar glomeruli of KO mice, compared with WT mice. The postsynaptic density around the terminals of mossy fibers was also increased in KO mice. Although there were no significant differences in locomotor ability between KO and WT animals in their home cages or in the open field, young adult KO mice had an increased grip strength and a tendency to exhibit better motor performance in balance-related tests compared with WT animals. Taken together, our results suggest that v-KIND is required for compact dendritic growth and proper excitatory synaptic connections in cerebellar granule cells, which are necessary for normal motor coordination and balance.
authors.affiliation: Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, Wako, Saitama, Japan.|Department of Anatomy, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kanehiro
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, Wako, Saitama, Japan.|Laboratory for Mental Biology, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Furuya
authors.affiliation: Research Resource Center, RIKEN Brain Science Institute, Wako, Saitama, Japan.|Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Sakamaki
authors.affiliation: Research Resource Center, RIKEN Brain Science Institute, Wako, Saitama, Japan.|Department of Physiology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Akagi
authors.affiliation: Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, Wako, Saitama, Japan.|School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
authors.forename: Yo
authors.initials: Y
authors.lastname: Shinoda
authors.affiliation: Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, Wako, Saitama, Japan.|Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Sadakata
authors.affiliation: Research Resource Center, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hashikawa
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Minami
authors.affiliation: Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Sano
authors.affiliation: Chromosome Engineering Team, Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Chiba, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, Wako, Saitama, Japan.|Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Teiichi
authors.identifier: http://orcid.org/0000-0002-9676-1888
authors.initials: T
authors.lastname: Furuichi
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D015415:Biomarkers; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000166:cytology* / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics; D011597:Psychomotor Performance; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D015415:Biomarkers; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; C511876:very-KIND protein, mouse