title: Karyopherin Alpha Proteins Regulate Oligodendrocyte Differentiation.
abstract: Proper regulation of the coordinated transcriptional program that drives oligodendrocyte (OL) differentiation is essential for central nervous system myelin formation and repair. Nuclear import, mediated in part by a group of karyopherin alpha (Kpna) proteins, regulates transcription factor access to the genome. Understanding how canonical nuclear import functions to control genomic access in OL differentiation may aid in the creation of novel therapeutics to stimulate myelination and remyelination. Here, we show that members of the Kpna family regulate OL differentiation, and may play distinct roles downstream of different pro-myelinating stimuli. Multiple family members are expressed in OLs, and their pharmacologic inactivation dose-dependently decreases the rate of differentiation. Additionally, upon differentiation, the three major Kpna subtypes (P/α2, Q/α3, S/α1) display differential responses to the pro-myelinating cues T3 and CNTF. Most notably, the Q/α3 karyopherin Kpna4 is strongly upregulated by CNTF treatment both compared with T3 treatment and other Kpna responses. Kpna4 inactivation results in inhibition of CNTF-induced OL differentiation, in the absence of changes in proliferation or viability. Collectively, these findings suggest that canonical nuclear import is an integral component of OL differentiation, and that specific Kpnas may serve vital and distinct functions downstream of different pro-myelinating cues.
authors.affiliation: Friedman Brain Institute, New York, New York, United States of America.|Corinne Goldsmith Dickinson Center for Multiple Sclerosis, New York, New York, United States of America.|Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, New York, United States of America.
authors.forename: Benjamin M
authors.identifier: http://orcid.org/0000-0002-9582-6088
authors.initials: BM
authors.lastname: Laitman
authors.affiliation: Friedman Brain Institute, New York, New York, United States of America.|Corinne Goldsmith Dickinson Center for Multiple Sclerosis, New York, New York, United States of America.|Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, New York, United States of America.
authors.forename: John N
authors.initials: JN
authors.lastname: Mariani
authors.affiliation: Friedman Brain Institute, New York, New York, United States of America.|Corinne Goldsmith Dickinson Center for Multiple Sclerosis, New York, New York, United States of America.|Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, New York, United States of America.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Friedman Brain Institute, New York, New York, United States of America.|Corinne Goldsmith Dickinson Center for Multiple Sclerosis, New York, New York, United States of America.|Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, New York, United States of America.
authors.forename: Setsu
authors.initials: S
authors.lastname: Sawai
authors.affiliation: Friedman Brain Institute, New York, New York, United States of America.|Corinne Goldsmith Dickinson Center for Multiple Sclerosis, New York, New York, United States of America.|Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, New York, United States of America.
authors.forename: Gareth R
authors.initials: GR
authors.lastname: John
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051379:Mice; D009836:Oligodendroglia / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology; D028901:alpha Karyopherins / Q000502:physiology*
chemical_list: D028901:alpha Karyopherins