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Nat Neurosci DOI:10.1038/nn.2855

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

Publication TypeJournal Article
Year of Publication2011
AuthorsFancy, SPJ, Harrington, EP, Yuen, TJ, Silbereis, JC, Zhao, C, Baranzini, SE, Bruce, CC, Otero, JJ, Huang, EJ, Nusse, R, Franklin, RJM, Rowitch, DH
JournalNat Neurosci
Date Published2011 Jun 26
KeywordsAdult, Animals, Animals, Newborn, Axin Protein, Basic Helix-Loop-Helix Transcription Factors, beta Catenin, beta-Galactosidase, Brain Injuries, Cell Differentiation, Cells, Cultured, Cerebellum, Cerebral Cortex, Corpus Callosum, Cytoskeletal Proteins, Demyelinating Diseases, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Gene Expression Regulation, Heterocyclic Compounds, 3-Ring, Humans, Hypoxia-Ischemia, Brain, Infant, Newborn, Ki-67 Antigen, Lysophosphatidylcholines, Male, Mice, Mice, Transgenic, Microscopy, Electron, Transmission, Multiple Sclerosis, Myelin Proteins, Myelin Sheath, Nerve Tissue Proteins, Neurons, Oligodendroglia, Organ Culture Techniques, Postmortem Changes, Spinal Cord, Stem Cells, Wnt Proteins

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.


Alternate JournalNat. Neurosci.
PubMed ID21706018
PubMed Central IDPMC3145042
Grant ListNS040511 / 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