The Transcriptional Activator Krüppel-Like Factor-6 Is Required for CNS Myelination (S10.007)

Objective: To determine the mechanism of action of Kruppel-like factor-6 (Klf6), a transcription factor found to be important for myelination. Background: Oligodendrocyte progenitors (OLP) are the main reservoir of myelinating and remyelinating cells in the CNS. Their differentiation into myelinating oligodendrocytes (OL) is a rate-limiting step in disease. Thus, understanding the OL differentiation and maturation pathway is vital to developing new treatments for demyelinating and dysmyelinating disorders. OLP differentiation occurs via a step-wise intrinsic transcriptional program, which can be modulated by pro-myelinating extrinsic factors, however the complex dynamics of this program are not fully characterized. Understanding the mechanisms that regulate the intrinsic program of differentiation may identify new strategies to enhance myelination and repair. Methods: Genome-wide analysis of chromatin occupancy (ChIP-Seq) of Klf6 and its transcriptional profile (RNA-Seq) has identified a program of Klf6-regulated genes. Using a mouse in which Klf6 inactivation is targeted to the OL lineage and OL cultures in which Klf6 is inactivated, we determine which targets are functionally critical to differentiation. Results: Klf6 is rapidly induced in 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 within a novel gp130-Klf axis that promotes viability and differentiation, in part, via control of nuclear trafficking. Klf6 acts directly and via induction of Klf4 to regulate the nuclear import factors Impα5 and Impα1. Interfering with this mechanism interrupts step-wise differentiation, with subsequent apoptosis. Validating significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and importin expression, OLP maturation arrest, apoptosis, and failure of CNS myelination. Conclusions: Our findings identify Klf6 as key in coordinating extrinsic inputs into OLP differentiation and essential to the success of CNS myelination. Disclosure: Dr. Laitman has nothing to disclose. Dr. Asp has nothing to disclose. Dr. Mariani has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Liu has nothing to disclose. Dr. Dutta has nothing to disclose. Dr. Chapouly has nothing to disclose. Dr. Horng has nothing to disclose. Dr. Kramer has nothing to disclose. Dr. Mitiku has nothing to disclose. Dr. Loo has nothing to disclose. Dr. Burlant has nothing to disclose. Dr. Pedre has nothing to disclose. Dr. Hara has nothing to disclose. Dr. Nudelman has nothing to disclose. Dr. Zaslavsky has nothing to disclose. Dr. Lee has nothing to disclose. Dr. Braun has nothing to disclose. Dr. Lu has nothing to disclose. Dr. Narla has nothing to disclose. Dr. Raine has nothing to disclose. Dr. Friedman has nothing to disclose. Dr. Casaccia has nothing to disclose. Dr. John has nothing to disclose.