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Ann Neurol DOI:10.1002/ana.23590

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

Publication TypeJournal Article
Year of Publication2012
AuthorsFancy, SPJ, Glasgow, SM, Finley, M, Rowitch, DH, Deneen, B
JournalAnn Neurol
Date Published2012 Aug
KeywordsAdenomatous Polyposis Coli Protein, Animals, Arabidopsis Proteins, Cell Differentiation, Cells, Cultured, Cerebral Cortex, Chromatin Immunoprecipitation, Disease Models, Animal, DNA-Binding Proteins, Electroporation, Embryo, Mammalian, Gene Expression Regulation, Developmental, Homeodomain Proteins, Humans, Hypoxia-Ischemia, Brain, Infant, Infant, Newborn, Intramolecular Transferases, Leukoencephalopathies, Lysophosphatidylcholines, Mice, Mice, Transgenic, Multiple Sclerosis, Myelin Basic Protein, NFI Transcription Factors, Oligodendroglia, Spinal Cord, Stem Cells, Time Factors, Transcription Factors

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.


Alternate JournalAnn. Neurol.
PubMed ID22807310
PubMed Central IDPMC3429638
Grant ListR01 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