Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination
Premyelinating oligodendrocytes are vulnerable to hypoxic injuries, especially during the neonatal period. Here, Fancy et al . find that the Wnt scaffolding molecule Axin2 is crucial for normal remyelination after hypoxic injuries and demonstrate that pharmacological inhibition of tankyrase, which s...
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Published in | Nature neuroscience Vol. 14; no. 8; pp. 1009 - 1016 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
01.08.2011
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Premyelinating oligodendrocytes are vulnerable to hypoxic injuries, especially during the neonatal period. Here, Fancy
et al
. find that the Wnt scaffolding molecule Axin2 is crucial for normal remyelination after hypoxic injuries and demonstrate that pharmacological inhibition of tankyrase, which stabilizes Axin2 levels, can promote oligodendrocyte differentiation and recovery after hypoxic and demyelinating injuries.
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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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Author Contributions S.P.J.F. helped conceive of 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. |
ISSN: | 1097-6256 1546-1726 |
DOI: | 10.1038/nn.2855 |