title: Neuronal Nuclear Membrane Budding Occurs during a Developmental Window Modulated by Torsin Paralogs.
abstract: DYT1 dystonia is a neurodevelopmental disease that manifests during a discrete period of childhood. The disease is caused by impaired function of torsinA, a protein linked to nuclear membrane budding. The relationship of NE budding to neural development and CNS function is unclear, however, obscuring its potential role in dystonia pathogenesis. We find NE budding begins and resolves during a discrete neurodevelopmental window in torsinA null neurons in vivo. The developmental resolution of NE budding corresponds to increased torsinB protein, while ablating torsinB from torsinA null neurons prevents budding resolution and causes lethal neural dysfunction. Developmental changes in torsinB also correlate with NE bud formation in differentiating DYT1 embryonic stem cells, and overexpression of torsinA or torsinB rescues NE bud formation in this system. These findings identify a torsinA neurodevelopmental window that is essential for normal CNS function and have important implications for dystonia pathogenesis and therapeutics.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Tanabe
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Liang
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: dauer@med.umich.edu.
authors.forename: William T
authors.initials: WT
authors.lastname: Dauer
mesh_terms: D000818:Animals; D004421:Dystonia / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D065886:Neurodevelopmental Disorders / Q000235:genetics / Q000503:physiopathology*; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009685:Nuclear Envelope / Q000378:metabolism* / Q000473:pathology
chemical_list: C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones; C400325:Tor1b protein, mouse