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Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination

Nature Neuroscience volume 14, pages 1009–1016 (2011)Cite this article

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Abstract

Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of brain injuries of the newborn that cause cerebral palsy and cognitive disabilities, as well as multiple sclerosis in adults. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults. Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting β-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination. The small molecule inhibitor XAV939, which targets the enzymatic activity of tankyrase, acted to stabilize Axin2 levels in OLPs from brain and spinal cord and accelerated their differentiation and myelination after hypoxic and demyelinating injury. Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process.

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Figure 1: AXIN2 mRNA expression identifies Wnt pathway activation in immature oligodendrocytes in neonatal human WMI.
Figure 2: Axin2 functions as a negative regulator of Wnt signaling in OLPs and promotes differentiation.
Figure 3: AXIN2 is expressed in OLPs in active multiple sclerosis lesions.
Figure 4: Axin2 function is essential for timely myelin repair.
Figure 5: Axin protein stabilization through small molecule tankyrase inhibition promotes OLP differentiation in vitro.
Figure 6: XAV939 treatment increases myelination, myelination following hypoxia and remyelination in ex vivo mouse cerebellar slice cultures.
Figure 7: XAV939 treatment markedly accelerates OLP differentiation and myelin regeneration during remyelination in vivo.

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Acknowledgements

We thank W. Birchmeier for Axin2-lacZ mice. This work was supported by a Promise 2010 grant from the National Multiple Sclerosis Society (to R.J.M.F. and D.H.R.), the United Kingdom Multiple Sclerosis Society (to R.J.M.F.), the US National Institutes of Health (NS040511 and NS047572 to D.H.R.) and the Medical Scientist Training Program at the University of California, San Francisco (to E.P.H.). S.E.B. is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society. R.N. and D.H.R. are Howard Hughes Medical Institute Investigators.

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Authors and Affiliations

  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, San Francisco, California, USA

    Stephen P J Fancy, Emily P Harrington, Tracy J Yuen, John C Silbereis, Jose J Otero & David H Rowitch

  2. Medical Scientist Training Program, University of California, San Francisco, California, USA

    Emily P Harrington

  3. MRC Centre for Stem Cell Biology and Regenerative Medicine and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK

    Chao Zhao, Charlotte C Bruce & Robin J M Franklin

  4. Department of Neurology, University of California, San Francisco, California, USA

    Sergio E Baranzini

  5. Department of Pathology, University of California, San Francisco, California, USA

    Jose J Otero & Eric J Huang

  6. Department of Developmental Biology and Howard Hughes Medical Institute, Stanford University, Stanford, California, USA

    Roel Nusse

  7. Division of Neonatology, University of California, San Francisco, California, USA

    David H Rowitch

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  1. Stephen P J Fancy
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Contributions

S.P.J.F. helped conceive the project and performed all experiments and analysis, with the exception of the following. E.P.H. performed and analyzed all experiments related to in vitro OLP cultures. T.J.Y. performed and analyzed the ex vivo cerebellar slice cultures. J.C.S. helped analyze Wnt pathway activation in murine hypoxic injury. C.Z. performed the electron microscopy and C.C.B. performed the G ratio analysis. S.E.B. performed bioinformatics. J.J.O. and E.J.H. procured human brain developmental tissue. R.J.M.F. and D.H.R. conceived the experiments and oversaw all aspects of the analysis. The paper was written by S.P.J.F., R.N., R.J.M.F. and D.H.R.

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Correspondence to David H Rowitch.

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Fancy, S., Harrington, E., Yuen, T. et al. Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nat Neurosci 14, 1009–1016 (2011). https://doi.org/10.1038/nn.2855

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