Evidence that nuclear factor IA inhibits repair after white matter injury

Authors

  • Stephen P. J. Fancy DVM, PhD,

    1. 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
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  • Stacey M. Glasgow PhD,

    1. Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, TX
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  • Meggie Finley BS,

    1. Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, TX
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  • David H. Rowitch MD, PhD,

    1. 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
    2. Division of Neonatology, University of California at San Francisco, San Francisco, CA
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  • Benjamin Deneen PhD

    Corresponding author
    1. Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, TX
    2. Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX
    • Center for Cell and Gene Therapy, Baylor College of Medicine N1120.06, One Baylor Plaza, Houston, TX 77030
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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. ANN NEUROL 2012;

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