Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination
| Autor: | Eric J. Huang, Jose Otero, Roel Nusse, Tracy J. Yuen, Stephen P.J. Fancy, Robin J.M. Franklin, John C. Silbereis, Charlotte C. Bruce, Sergio E. Baranzini, Emily P. Harrington, David H. Rowitch, Chao Zhao |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
Cerebellum Cellular differentiation Neurodegenerative Transgenic Corpus Callosum Myelin Mice Heterocyclic Compounds Basic Helix-Loop-Helix Transcription Factors Psychology Myelin Sheath beta Catenin Cerebral Cortex Neurons Pediatric Microscopy Cultured General Neuroscience Stem Cells Wnt signaling pathway Brain Cell Differentiation Injuries and accidents Oligodendroglia medicine.anatomical_structure Spinal Cord 5.1 Pharmaceuticals Neurological Female Cognitive Sciences medicine.symptom Drug Development of treatments and therapeutic interventions Myelin Proteins Adult Multiple Sclerosis Cells Nerve Tissue Proteins Brain damage Biology 3-Ring Electron Autoimmune Disease Article White matter Dose-Response Relationship Organ Culture Techniques Axin Protein Hypoxia-Ischemia medicine Animals Humans Transmission Remyelination Neurology & Neurosurgery Animal Multiple sclerosis Neurosciences Lysophosphatidylcholines Infant Oligodendrocyte Transcription Factor 2 Perinatal Period - Conditions Originating in Perinatal Period medicine.disease Newborn beta-Galactosidase Brain Disorders Wnt Proteins Cytoskeletal Proteins Ki-67 Antigen Gene Expression Regulation Brain Injuries Postmortem Changes Disease Models Injury (total) Accidents/Adverse Effects Neuroscience Demyelinating Diseases |
| Zdroj: | Nature neuroscience Nature neuroscience, vol 14, iss 8 |
| ISSN: | 1546-1726 1097-6256 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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