In multiple sclerosis (MS), demyelination of axons produces conduction block and symptoms including paralysis and blindness, while myelin repair (remyelination) brings functional recovery. A key goal in MS research is to enhance remyelination, which occurs spontaneously but is inefficient, especially in the later stages of the disease. Oligodendrocyte progenitors (OLP) are the major reservoir of remyelinating cells. Their differentiation occurs via an intrinsic transcriptional program, which is promoted by extrinsic pathways, including Stat3, Smad3, Akt-PI3kinase, Erk1/2 and Tralpha1/RXR signaling. Elucidating how these pathways promote differentiation may identify new strategies to enhance remyelination. Recently, we identified the Kr?ppel-like transcriptional activator Klf6 as an essential coordinator of CNS myelination. Importantly, our data also indicate that Klf6 signaling links extrinsic pathways to the intrinsic differentiation program. Notably, key extrinsic pro-myelinating pathways (Stat3 and Smad3 signaling) strongly induce Klf6 in differentiating cells, and Klf6 over-expression accelerates differentiation. Conversely, Klf6 deletion in vitro or in vivo blocks vital steps in differentiation, and leads to complete failure of myelination. This pathology partly mimics deficits resulting from Stat3 or Smad3 inactivation. The effects of Klf6 are restricted to the differentiation program - inactivation in proliferating or mature cells produces o pathology. Our data further suggest important roles in adults, in normal myelin turnover and, critically, in remyelination. Klf6 is strongly induced in remyelinating lesions, paralleling activaion of extrinsic pro-myelinating pathways. To understand Klf6 mechanism of action, we have now used genome-wide analysis of chromatin occupancy, and transcriptional profiling. This work has identified a program of both novel and anticipated Klf6- regulated genes. Importantly, their roles propose Klf6 contributions to sequential steps in differentiation. Moreover, our data further indicate that Klf6 binding also recruits epigenetic coactivators to target loci, and that these enhance transactivation of its transcriptional targets. Together, our findings suggest that Klf6 may form complexes with transcriptional and epigenetic coactivators, to promote differentiation and myelin formation. In this proposal, we will test the central hypothesis that Klf6 linkage of extrinsic regulators with the intrinsic differentiation program is essential for CNS remyelination. We propose three Specific Aims.
In Aim 1, we will test the extent to which extrinsic pro-myelinating factors promote differentiation via Klf6 signaling.
In Aim 2, we will define the mechanism of action by which Klf6 controls differentiation.
In Aim 3, we will then test the role of Klf6 signaling in adult white matter, in normal myelin turnover and, critically, in remyelination. This work will define a new mechanism required for myelin formation, and which may be vital for repair. Elucidating how extrinsic pathways promote maturation may identify new strategies to enhance remyelination.

Public Health Relevance

A key goal in multiple sclerosis research is to enhance myelin repair (remyelination); which results from differentiation of oligodendrocyte progenitors (OLP) and brings functional recovery in patients; but is inefficient. Importantly; we have identified a novel transcriptional and epigenetic program driven by the Kr?ppel-like transcriptional activator Klf6; as essential for OLP differentiation and CNS myelination; and our data further suggest relevance to repair. In this proposal; we will define how this program is regulated; how it drives differentiation; and its role in the adult CNS in myelin turnover and; critically; in remyelination

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
Zip Code
Laitman, Benjamin M; John, Gareth R (2015) Understanding How Exercise Promotes Cognitive Integrity in the Aging Brain. PLoS Biol 13:e1002300
Chapouly, Candice; Tadesse Argaw, Azeb; Horng, Sam et al. (2015) Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions. Brain 138:1548-67
Dutta, Dipankar J; Zameer, Andleeb; Mariani, John N et al. (2014) Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination. Development 141:2414-28