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.

doi:10.1371/journal.pbio.1002467

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PLOS BIOLOGY. 2016, vol. 14, n° 5, p. e1002467

Resumen en inglés

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.< Leer menos

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Palabras clave en inglés

Alpha Karyopherins

Animals

Cell Differentiation

Cell Survival

Central Nervous System

Chromatin

Cytokine Receptor Gp130

Developmental

Embryo

Gene Expression Regulation

Inbred C57bl

Kruppel-Like Factor 6

Kruppel-Like Transcription Factors

Mammalian

Mice

Myelin Sheath

Oligodendroglia

Proto-Oncogene Proteins

Signal Transduction

Stat3 Transcription Factor

Stem Cells

Transgenic

URI

https://oskar-bordeaux.fr/handle/20.500.12278/11529

DOI

http://dx.doi.org/10.1371/journal.pbio.1002467

Centros de investigación

Biologie des maladies cardiovasculaires (BMC) - UMR 1034

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