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


CONCLUSIONS
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.
Departments of Pediatrics and Neurosurgery, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA, USA.
Stephen P J
SP
Fancy
Stacey M
SM
Glasgow
Meggie
M
Finley
David H
DH
Rowitch
Benjamin
B
Deneen
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000818:Animals; D029681:Arabidopsis Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018274:Electroporation; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism; D007223:Infant; D007231:Infant, Newborn; D019751:Intramolecular Transferases / Q000378:metabolism; D056784:Leukoencephalopathies / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D008244:Lysophosphatidylcholines / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D029681:Arabidopsis Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D008244:Lysophosphatidylcholines; C078341:MYT1 protein, human; D004676:Myelin Basic Protein; D051839:NFI Transcription Factors; C497592:NFIA protein, human; C491536:NKX3-2 protein, human; D014157:Transcription Factors; D019751:Intramolecular Transferases; C568454:marneral synthase, Arabidopsis