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

• Published in: PLoS biology Vol. 14; no. 5; p. e1002467
• Main Authors: Laitman, Benjamin M, Asp, Linnéa, Mariani, John N, Zhang, Jingya, Liu, Jia, Sawai, Setsu, Chapouly, Candice, Horng, Sam, Kramer, Elisabeth G, Mitiku, Nesanet, Loo, Hannah, Burlant, Natalie, Pedre, Xiomara, Hara, Yuko, Nudelman, German, Zaslavsky, Elena, Lee, Young-Min, Braun, David A, Lu, Q Richard, Narla, Goutham, Raine, Cedric S, Friedman, Scott L, Casaccia, Patrizia, John, Gareth R
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2016; Public Library of Science (PLoS)
• Subjects: alpha Karyopherins - metabolism; Animals; Apoptosis; Ataxia; Biology and Life Sciences; Cell Differentiation; Cell Survival - genetics; Central Nervous System - metabolism; Charitable foundations; Chromatin - metabolism; Cytokine Receptor gp130 - genetics; Cytokine Receptor gp130 - metabolism; Embryo, Mammalian - cytology; Embryo, Mammalian - metabolism; Experiments; Funding; Gene Expression Regulation, Developmental; Growth factors; Human health and pathology; Kruppel-Like Factor 6; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Life Sciences; Medicine and Health Sciences; Mice, Inbred C57BL; Mice, Transgenic; Microscopy; Multiple sclerosis; Myelin Sheath - metabolism; Nervous system; Oligodendroglia - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Rodents; Signal Transduction; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Stem Cells - metabolism; Studies; Transcription factors; Developmental; Chromatin; Embryo; Kruppel-Like Factor 6; Signal Transduction; Cell Survival; Cytokine Receptor Gp130; Gene Expression Regulation; Transgenic; Stat3 Transcription Factor; Inbred C57bl; Mammalian; Kruppel-Like Transcription Factors; Stem Cells; Alpha Karyopherins; Animals; Central Nervous System; Myelin Sheath; Oligodendroglia; Cell Differentiation; Mice; Proto-Oncogene Proteins; Article RECHERCHE
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.1002467

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.