The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination

Benjamin M. Laitman, Linnéa Asp, John N. Mariani, Jingya Zhang, Jia Liu, Setsu Sawai, Candice Chapouly, Sam Horng, Elisabeth G. Kramer, Nesanet Mitiku, Hannah Loo, Natalie Burlant, Xiomara Pedre, Yuko Hara, German Nudelman, Elena Zaslavsky, Young Min Lee, David A. Braun, Q. Richard Lu, Goutham NarlaCedric S. Raine, Scott L. Friedman, Patrizia Casaccia, Gareth R. John

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination.

Original languageEnglish (US)
Article numbere1002467
JournalPLoS biology
Volume14
Issue number5
DOIs
StatePublished - May 23 2016

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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    Laitman, B. M., Asp, L., Mariani, J. N., Zhang, J., Liu, J., Sawai, S., Chapouly, C., Horng, S., Kramer, E. G., Mitiku, N., Loo, H., Burlant, N., Pedre, X., Hara, Y., Nudelman, G., Zaslavsky, E., Lee, Y. M., Braun, D. A., Lu, Q. R., ... John, G. R. (2016). The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination. PLoS biology, 14(5), [e1002467]. https://doi.org/10.1371/journal.pbio.1002467