title: The progeroid gene BubR1 regulates axon myelination and motor function.
abstract: Myelination, the process by which oligodendrocytes form the myelin sheath around axons, is key to axonal signal transduction and related motor function in the central nervous system (CNS). Aging is characterized by degenerative changes in the myelin sheath, although the molecular underpinnings of normal and aberrant myelination remain incompletely understood. Here we report that axon myelination and related motor function are dependent on BubR1, a mitotic checkpoint protein that has been linked to progeroid phenotypes when expressed at low levels and healthy lifespan when overabundant. We found that oligodendrocyte progenitor cell proliferation and oligodendrocyte density is markedly reduced in mutant mice with low amounts of BubR1 (BubR1H/Hmice), causing axonal hypomyelination in both brain and spinal cord. Expression of essential myelin-related genes such as MBP and PLP1 was significantly reduced in these tissues. Consistent with defective myelination,BubR1H/Hmice exhibited various motor deficits, including impaired motor strength, coordination, and balance, irregular gait patterns and reduced locomotor activity. Collectively, these data suggest that BubR1 is a key determinant of oligodendrocyte production and function and provide a molecular entry point to understand age-related degenerative changes in axon myelination.
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Chan-Il
authors.initials: CI
authors.lastname: Choi
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Ki Hyun
authors.initials: KH
authors.lastname: Yoo
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Syed Mohammed Qasim
authors.initials: SM
authors.lastname: Hussaini
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Byeong Tak
authors.initials: BT
authors.lastname: Jeon
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: John
authors.initials: J
authors.lastname: Welby
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Gan
authors.affiliation: Department of Physical Medicine and Rehabilitation, Rehabilitation Medicine Research Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Isobel A
authors.initials: IA
authors.lastname: Scarisbrick
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Baker
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: van Deursen
authors.affiliation: Departments of Neurology and Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Moses
authors.initials: M
authors.lastname: Rodriguez
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.|Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Mi-Hyeon
authors.initials: MH
authors.lastname: Jang
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D005684:Gait / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics*; D009186:Myelin Sheath / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases
keywords: BubR1; corpus callosum; motor function; myelination; oligodendrocytes; spinal cord