Evidence that nuclear factor IA inhibits repair after white matter injury.

Ann Neurol
Authors
Keywords
Abstract

OBJECTIVE: 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.

METHODS: 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.

RESULTS: 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.

INTERPRETATION: 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.

Year of Publication
2012
Journal
Ann Neurol
Volume
72
Issue
2
Pages
224-33
Date Published
2012 Aug
ISSN
1531-8249
URL
DOI
10.1002/ana.23590
PubMed ID
22807310
PubMed Central ID
PMC3429638
Links
Grant list
R01 NS040511 / NS / NINDS NIH HHS / United States
T32 HL092332 / HL / NHLBI NIH HHS / United States
R01 NS059893 / NS / NINDS NIH HHS / United States
R01 NS071153 / NS / NINDS NIH HHS / United States
R01 NS071153-01 / NS / NINDS NIH HHS / United States