title: Katanin p80 regulates human cortical development by limiting centriole and cilia number.
abstract: Katanin is a microtubule-severing complex whose catalytic activities are well characterized, but whose in vivo functions are incompletely understood. Human mutations in KATNB1, which encodes the noncatalytic regulatory p80 subunit of katanin, cause severe microlissencephaly. Loss of Katnb1 in mice confirms essential roles in neurogenesis and cell survival, while loss of zebrafish katnb1 reveals specific roles for katnin p80 in early and late developmental stages. Surprisingly, Katnb1 null mutant mouse embryos display hallmarks of aberrant Sonic hedgehog signaling, including holoprosencephaly. KATNB1-deficient human cells show defective proliferation and spindle structure, while Katnb1 null fibroblasts also demonstrate a remarkable excess of centrioles, with supernumerary cilia but deficient Hedgehog signaling. Our results reveal unexpected functions for KATNB1 in regulating overall centriole, mother centriole, and cilia number, and as an essential gene for normal Hedgehog signaling during neocortical development.
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Harvard MD-PhD MSTP Program, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Wen F
authors.initials: WF
authors.lastname: Hu
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648, Singapore.
authors.forename: Oz
authors.initials: O
authors.lastname: Pomp
authors.affiliation: Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha, 3050, Qatar.
authors.forename: Tawfeg
authors.initials: T
authors.lastname: Ben-Omran
authors.affiliation: Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kodani
authors.affiliation: Department of Orthopedic Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Katrin
authors.initials: K
authors.lastname: Henke
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Ganeshwaran H
authors.initials: GH
authors.lastname: Mochida
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Yu
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mollie B
authors.initials: MB
authors.lastname: Woodworth
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648, Singapore.
authors.forename: Carine
authors.initials: C
authors.lastname: Bonnard
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648, Singapore.
authors.forename: Grace Selva
authors.initials: GS
authors.lastname: Raj
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648, Singapore.
authors.forename: Thong Teck
authors.initials: TT
authors.lastname: Tan
authors.affiliation: Department of Genetic Medicine and Development, Geneva University, Geneva 1211, Switzerland.
authors.forename: Hanan
authors.initials: H
authors.lastname: Hamamy
authors.affiliation: Department of Paediatrics, Faculty of Medicine, University of Jordan, Amman, 11942, Jordan.
authors.forename: Amira
authors.initials: A
authors.lastname: Masri
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648, Singapore.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shboul
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
authors.forename: Muna
authors.initials: M
authors.lastname: Al Saffar
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Partlow
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Dosari
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
authors.forename: Anas
authors.initials: A
authors.lastname: Alazami
authors.affiliation: Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alowain
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.affiliation: Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jeremy F
authors.initials: JF
authors.lastname: Reiter
authors.affiliation: Department of Orthopedic Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: harris@genetics.med.harvard.edu.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Harris
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648, Singapore; Institute of Molecular and Cellular Biology, A(∗)STAR, Singapore 138648, Singapore; Department of Paediatrics, National University of Singapore, Singapore 119260, Singapore. Electronic address: bruno@reversade.com.
authors.forename: Bruno
authors.initials: B
authors.lastname: Reversade
authors.affiliation: Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Harvard MD-PhD MSTP Program, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: christopher.walsh@childrens.harvard.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002502:Centrioles / Q000235:genetics / Q000502:physiology*; D002540:Cerebral Cortex / Q000002:abnormalities / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D002923:Cilia / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000074201:Katanin; D051379:Mice; D008831:Microcephaly / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D012326:RNA Splicing / Q000235:genetics; D044465:White People / Q000235:genetics; D015027:Zebrafish
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D000251:Adenosine Triphosphatases; D000074201:Katanin