Evidence that nuclear factor IA inhibits repair after white matter injury
Version of Record online: 17 JUL 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 72, Issue 2, pages 224–233, August 2012
How to Cite
Fancy, S. P. J., Glasgow, S. M., Finley, M., Rowitch, D. H. and Deneen, B. (2012), Evidence that nuclear factor IA inhibits repair after white matter injury. Ann Neurol., 72: 224–233. doi: 10.1002/ana.23590
- Issue online: 27 AUG 2012
- Version of Record online: 17 JUL 2012
- Accepted manuscript online: 19 MAR 2012 03:33AM EST
- Manuscript Accepted: 9 MAR 2012
- Manuscript Revised: 9 FEB 2012
- Manuscript Received: 12 DEC 2011
- National Multiple Sclerosis Society
- Gillson Longenbaugh Foundation
- NIH. Grant Number: R01 NS071153
- NIH NHLBl [NINDS]. Grant Numbers: R01 NS040511, R01 NS059893
- Baylor College of Medicine IDDRC. Grant Number: HD024064
Chronic demyelination can result in axonopathy and is associated with human neurological conditions such as multiple sclerosis (MS) in adults and cerebral palsy in infants. In these disorders, myelin regeneration is inhibited by impaired differentiation of oligodendrocyte progenitors into myelin-producing oligodendrocytes. However, regulatory factors relevant in human myelin disorders and in myelin regeneration remain poorly understood. Here we have investigated the role of the transcription factor nuclear factor IA (NFIA) in oligodendrocyte progenitor differentiation during developmental and regenerative myelination.
NFIA expression patterns in human neonatal hypoxic–ischemic encephalopathy (HIE) and MS as well as developmental expression in mice were evaluated. Functional studies during remyelination were performed using a lysolecithin model, coupled with lentiviral misexpression of NFIA. The role of NFIA during oligodendrocyte lineage development was characterized using chick and mouse models and in vitro culture of oligodendrocyte progenitors. Biochemical mechanism of NFIA function was evaluated using chromatin immunoprecipitation and reporter assays.
NFIA is expressed in oligodendrocyte progenitors, but not differentiated oligodendrocytes during mouse embryonic development. Examination of NFIA expression in white matter lesions of human newborns with neonatal HIE, as well active MS lesions in adults, revealed that it is similarly expressed in oligodendrocyte progenitors and not oligodendrocytes. Functional studies indicate that NFIA is sufficient to suppress oligodendrocyte progenitor differentiation during adult remyelination and embryonic development through direct repression of myelin gene expression.
These studies suggest that NFIA participates in the control of oligodendrocyte progenitor differentiation and may contribute to the inhibition of remyelination in human myelin disorders. ANN NEUROL 2012;