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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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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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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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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DOI: https://doi.org/10.1038/nn.2855
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