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

Overview

Journal PLoS Biol

Specialty Biology

Date 2016 May 24

PMID 27213272

Citations 28

Authors

Benjamin M Laitman

Linnea 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 Narla

Cedric S Raine

Scott L Friedman

Patrizia Casaccia

Gareth R John

Affiliations

Soon will be listed here.

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.

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