Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS

  1. Stephen P.J. Fancy1,2,
  2. Sergio E. Baranzini3,
  3. Chao Zhao2,
  4. Dong-In Yuk4,
  5. Karen-Amanda Irvine5,
  6. Sovann Kaing1,
  7. Nader Sanai5,
  8. Robin J.M. Franklin2,8 and
  9. David H. Rowitch1,5,6,7
  1. 1Institute for Regeneration Medicine and Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, California 94143, USA;
  2. 2MRC Centre for Stem Cell Biology and Regenerative Medicine and Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, United Kingdom;
  3. 3Department of Neurology, University of California at San Francisco, San Francisco, California 94143, USA;
  4. 4Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
  5. 5Department of Neurosurgery, University of California at San Francisco, San Francisco, California 94143, USA;
  6. 6Department of Pediatrics, University of California at San Francisco, San Francisco, California 94143, USA

    Abstract

    The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that ∼50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesioned—but not normal—adult white matter. We report that β-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of Wnt–β-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of β-catenin in the oligodendrocyte lineage in vivo and (2) findings from APCMin mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt–β-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders.

    Keywords

    Footnotes

    • 7 Corresponding authors.

      E-MAIL rowitchd{at}peds.ucsf.edu; FAX (415) 476-9976.

    • 8 E-MAIL rjf1000{at}cam.ac.uk; FAX 44-1223-337610.

    • Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1806309.

    • Supplemental material is available at http://www.genesdev.org.

      • Received March 30, 2009.
      • Accepted May 19, 2009.
    • Freely available online through the Genes & Development Open Access option.

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