title: Katanin p80, NuMA and cytoplasmic dynein cooperate to control microtubule dynamics.
abstract: Human mutations in KATNB1 (p80) cause severe congenital cortical malformations, which encompass the clinical features of both microcephaly and lissencephaly. Although p80 plays critical roles during brain development, the underlying mechanisms remain predominately unknown. Here, we demonstrate that p80 regulates microtubule (MT) remodeling in combination with NuMA (nuclear mitotic apparatus protein) and cytoplasmic dynein. We show that p80 shuttles between the nucleus and spindle pole in synchrony with the cell cycle. Interestingly, this striking feature is shared with NuMA. Importantly, p80 is essential for aster formation and maintenance in vitro. siRNA-mediated depletion of p80 and/or NuMA induced abnormal mitotic phenotypes in cultured mouse embryonic fibroblasts and aberrant neurogenesis and neuronal migration in the mouse embryonic brain. Importantly, these results were confirmed in p80-mutant harboring patient-derived induced pluripotent stem cells and brain organoids. Taken together, our findings provide valuable insights into the pathogenesis of severe microlissencephaly, in which p80 and NuMA delineate a common pathway for neurogenesis and neuronal migration via MT organization at the centrosome/spindle pole.
authors.affiliation: Department of Genetic Disease Research, Osaka City University, Graduate School of Medicine, Asahi-machi 1-4-3, Abeno, Osaka 545-8585, Japan.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Jin
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, Singapore.
authors.forename: Oz
authors.initials: O
authors.lastname: Pomp
authors.affiliation: Department of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Shinoda
authors.affiliation: Department of Genetic Disease Research, Osaka City University, Graduate School of Medicine, Asahi-machi 1-4-3, Abeno, Osaka 545-8585, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Toba
authors.affiliation: Advanced ICT Research Institute, National Institute of Information and Communications Technology, Kobe, Hyogo 651-2492, Japan.|CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Torisawa
authors.affiliation: Advanced ICT Research Institute, National Institute of Information and Communications Technology, Kobe, Hyogo 651-2492, Japan.|CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0076, Japan.
authors.forename: Ken'ya
authors.initials: K
authors.lastname: Furuta
authors.affiliation: Advanced ICT Research Institute, National Institute of Information and Communications Technology, Kobe, Hyogo 651-2492, Japan.|CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0076, Japan.|Graduate School of Life Science, University of Hyogo, Harima Science Park City, Hyogo 678-1297, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Oiwa
authors.affiliation: Department of Bioscience and Bioinformatics, Faculty of Computer Science and Systems Engineering, Kyushu Institute of Technology, Kawazu 680-4, Iizuka, Fukuoka 820-850, Japan.|JST-SENTAN, 4-1-8, Honcho, Kawaguchi, Saitama 332-0012, Japan.|JST-CREST, 4-1-8, Honcho, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Yasunaga
authors.affiliation: Division of Centrosome Biology, Department of Molecular Genetics, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka, 411-8540, Japan.
authors.forename: Daiju
authors.initials: D
authors.lastname: Kitagawa
authors.affiliation: Department of Cell Biology, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Matsumura
authors.affiliation: Department of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan.
authors.forename: Takaki
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, Singapore.
authors.forename: Thong Teck
authors.initials: TT
authors.lastname: Tan
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, Singapore.|Institute of Molecular and Cellular Biology, A*STAR, Singapore 138648, Singapore.|Department of Paediatrics, National University of Singapore, Singapore 119260, Singapore.
authors.forename: Bruno
authors.initials: B
authors.lastname: Reversade
authors.affiliation: Department of Genetic Disease Research, Osaka City University, Graduate School of Medicine, Asahi-machi 1-4-3, Abeno, Osaka 545-8585, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Hirotsune
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D004398:Dyneins / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D000074201:Katanin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009421:Nervous System Malformations / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C000628834:Katnb1 protein, mouse; D009687:Nuclear Proteins; C489080:Numa1 protein, mouse; D034741:RNA, Small Interfering; D000251:Adenosine Triphosphatases; C000620002:KATNB1 protein, human; D004398:Dyneins; D000074201:Katanin