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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Animals, Newborn
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Axin Protein
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Brain Injuries / etiology
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Brain Injuries / metabolism*
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Brain Injuries / therapy*
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Cells, Cultured
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Cerebellum / drug effects
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Cerebellum / metabolism
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Cerebellum / ultrastructure
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Cerebral Cortex / cytology
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Corpus Callosum / drug effects
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Corpus Callosum / metabolism
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Cytoskeletal Proteins / deficiency
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Cytoskeletal Proteins / metabolism*
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Demyelinating Diseases / chemically induced
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Demyelinating Diseases / pathology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Female
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Gene Expression Regulation / genetics
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Gene Expression Regulation / physiology*
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Heterocyclic Compounds, 3-Ring / pharmacology
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Heterocyclic Compounds, 3-Ring / therapeutic use
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Humans
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Hypoxia-Ischemia, Brain / metabolism
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Hypoxia-Ischemia, Brain / pathology
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Hypoxia-Ischemia, Brain / therapy
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Infant, Newborn
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Ki-67 Antigen / metabolism
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Lysophosphatidylcholines / toxicity
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Male
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Mice
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Mice, Transgenic
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Microscopy, Electron, Transmission
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Multiple Sclerosis / complications
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Multiple Sclerosis / pathology
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Multiple Sclerosis / therapy
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Myelin Proteins / genetics
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Myelin Proteins / metabolism*
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Myelin Proteins / therapeutic use
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Myelin Sheath / drug effects
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Myelin Sheath / pathology
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Myelin Sheath / ultrastructure
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurons / drug effects
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Oligodendrocyte Transcription Factor 2
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Oligodendroglia / drug effects
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Oligodendroglia / physiology
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Organ Culture Techniques
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Postmortem Changes
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Spinal Cord / drug effects
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Spinal Cord / physiology
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Stem Cells / drug effects
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Wnt Proteins / genetics
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Wnt Proteins / metabolism
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beta Catenin / genetics
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beta Catenin / metabolism
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beta-Galactosidase / genetics
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beta-Galactosidase / metabolism
Substances
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AXIN2 protein, human
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Axin Protein
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Basic Helix-Loop-Helix Transcription Factors
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Cytoskeletal Proteins
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Heterocyclic Compounds, 3-Ring
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Ki-67 Antigen
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Lysophosphatidylcholines
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Myelin Proteins
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Nerve Tissue Proteins
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OLIG2 protein, human
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Oligodendrocyte Transcription Factor 2
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Wnt Proteins
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XAV939
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beta Catenin
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beta-Galactosidase