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

Nat Neurosci
Authors
Keywords
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.

Year of Publication
2011
Journal
Nat Neurosci
Volume
14
Issue
8
Pages
1009-16
Date Published
2011 Jun 26
ISSN
1546-1726
URL
DOI
10.1038/nn.2855
PubMed ID
21706018
PubMed Central ID
PMC3145042
Links
Grant list
NS040511 / NS / NINDS NIH HHS / United States
R01 NS040511 / NS / NINDS NIH HHS / United States
NS047572 / NS / NINDS NIH HHS / United States
Howard Hughes Medical Institute / United States
R01 NS040511-12 / NS / NINDS NIH HHS / United States