The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination
| Autor: | Elena Zaslavsky, Patrizia Casaccia, Goutham Narla, Youngmin A. Lee, Sam Horng, Xiomara Pedre, Yuko Hara, John N. Mariani, Benjamin M. Laitman, German Nudelman, Q. Richard Lu, Cedric S. Raine, Linnea Asp, Elisabeth G. Kramer, Candice Chapouly, Jingya Zhang, Jia Liu, David A. Braun, Nesanet Mitiku, Setsu Sawai, Scott L. Friedman, Gareth R. John, Hannah Loo, Natalie Burlant |
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| Přispěvatelé: | Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2016 |
| Předmět: |
Central Nervous System
0301 basic medicine Embryology Cellular differentiation Gene Expression Apoptosis Inbred C57bl Nervous System Transgenic Mice 0302 clinical medicine Animal Cells Medicine and Health Sciences Cytokine Receptor gp130 Developmental Biology (General) 10. No inequality Myelin Sheath Neurons Motor Neurons Regulation of gene expression Cell Death Chromosome Biology Stem Cells General Neuroscience Article RECHERCHE Gene Expression Regulation Developmental Cell Differentiation Chromatin Cell biology Oligodendroglia medicine.anatomical_structure Spinal Cord Embryo Cell Processes Epigenetics Anatomy Cellular Types Signal transduction General Agricultural and Biological Sciences Neuronal Differentiation Research Article Signal Transduction STAT3 Transcription Factor alpha Karyopherins QH301-705.5 Cell Survival Kruppel-Like Transcription Factors Mice Transgenic Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Proto-Oncogene Proteins Genetics Kruppel-Like Factor 6 medicine Animals Transcription factor General Immunology and Microbiology Mammalian Embryos Oligodendrocyte differentiation Biology and Life Sciences Alpha Karyopherins Cell Biology Embryo Mammalian Oligodendrocyte Mice Inbred C57BL Neuroanatomy 030104 developmental biology Gene Expression Regulation Cellular Neuroscience Immunology [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology 030217 neurology & neurosurgery Developmental Biology Neuroscience |
| Zdroj: | BASE-Bielefeld Academic Search Engine PLoS Biology PLoS Biology, Vol 14, Iss 5, p e1002467 (2016) Plos Biology Plos Biology, In press, 14 (5), pp.e1002467. ⟨10.1371/journal.pbio.1002467⟩ |
| ISSN: | 1545-7885 |
| DOI: | 10.1371/journal.pbio.1002467 |
| Popis: | 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. During the development of white matter in the central nervous system, the transcription factor Klf6 coordinates pro-myelinating effects of gp130-Stat3 signaling, and promotes oligodendrocyte differentiation in part via control of nuclear trafficking. Author Summary Myelin, a membranous sheet that surrounds the axons of neurons and facilitates the transmission of nerve impulses, is formed by oligodendrocytes in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS). Failure to myelinate, or demyelination, produces the symptoms of serious diseases such as leukodystrophies and multiple sclerosis. This study identifies a novel and essential regulator of myelin formation in the CNS: the transcriptional activator Krüppel-like factor-6 (Klf6). We show that Klf6 acts as a control point through which pro-myelinating signals regulate the development of oligodendrocytes from oligodendrocyte progenitor cells. Growth factors of the gp130 family are known to promote differentiation and survival of oligodendrocytes, via activation of the transcription factor Stat3, but the mechanistic details of how they do it remain unclear. Our findings show that Klf6 is induced in oligodendrocyte progenitors by gp130 growth factors, and promotes differentiation. Furthermore, oligodendrocyte progenitor cells in which Klf6 is inactivated do not mature, fail to form myelin, and eventually die. We also uncover that upon gp130 signaling, Klf6 activates the nuclear import factor importin-α5 (Impα5), a key controller of trafficking into the nucleus in the CNS. Notably, inactivation of Impα5 recapitulates the features of silencing Klf6, whereas Impα5 expression can partially rescue differentiation in Klf6-deficient oligodendrocyte progenitors. Finally, inactivation of Stat3 in oligodendrocyte progenitors produces defective Klf6 and Impα5 expression and myelination failure, strongly resembling the features produced by Klf6 inactivation. Collectively, these results establish a connection between gp130-Stat3 signaling and importin-based control of nuclear trafficking, which is essential for myelination in the CNS, and places Klf6 as a key coordinator of these events. |
| Databáze: | OpenAIRE |
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