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

• Published in: Nature neuroscience Vol. 14; no. 8; pp. 1009 - 1016
• Main Authors: Rowitch, David H, Fancy, Stephen P J, Harrington, Emily P, Yuen, Tracy J, Silbereis, John C, Zhao, Chao, Baranzini, Sergio E, Bruce, Charlotte C, Otero, Jose J, Huang, Eric J, Nusse, Roel, Franklin, Robin J M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2011; Nature Publishing Group
• Subjects: 631/378/2606; 692/699/375/1345; 692/699/375/1411; 692/700/565/1436/2185; Adult; Animal Genetics and Genomics; Animals; Animals, Newborn; Axin Protein; Basic Helix-Loop-Helix Transcription Factors - genetics; Behavioral Sciences; beta Catenin - genetics; beta Catenin - metabolism; beta-Galactosidase - genetics; beta-Galactosidase - metabolism; Binding proteins; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Brain Injuries - etiology; Brain Injuries - metabolism; Brain Injuries - therapy; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cells, Cultured; Cerebellum - drug effects; Cerebellum - metabolism; Cerebellum - ultrastructure; Cerebral Cortex - cytology; Corpus Callosum - drug effects; Corpus Callosum - metabolism; Cytoskeletal Proteins - deficiency; Cytoskeletal Proteins - metabolism; Demyelinating Diseases - chemically induced; Demyelinating Diseases - pathology; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Expression Regulation - genetics; Gene Expression Regulation - physiology; Health aspects; Heterocyclic Compounds, 3-Ring - pharmacology; Heterocyclic Compounds, 3-Ring - therapeutic use; Humans; Hypoxia-Ischemia, Brain - metabolism; Hypoxia-Ischemia, Brain - pathology; Hypoxia-Ischemia, Brain - therapy; Infant, Newborn; Infants (Newborn); Injuries; Ki-67 Antigen - metabolism; Lysophosphatidylcholines - toxicity; Male; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Multiple Sclerosis - complications; Multiple Sclerosis - pathology; Multiple Sclerosis - therapy; Myelin Proteins - genetics; Myelin Proteins - metabolism; Myelin Proteins - therapeutic use; Myelin Sheath - drug effects; Myelin Sheath - pathology; Myelin Sheath - ultrastructure; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology; Neurons - drug effects; Neurosciences; Oligodendrocyte Transcription Factor 2; Oligodendroglia - drug effects; Oligodendroglia - physiology; Organ Culture Techniques; Physiological aspects; Postmortem Changes; Spinal Cord - drug effects; Spinal Cord - physiology; Stem Cells - drug effects; Wnt Proteins - genetics; Wnt Proteins - metabolism; United States; United Kingdom
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.2855

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.