title: Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination.
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.
authors.affiliation: Department of Pediatrics and Neurosurgery, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, California, USA.
authors.forename: Stephen P J
authors.initials: SP
authors.lastname: Fancy
authors.forename: Emily P
authors.initials: EP
authors.lastname: Harrington
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Yuen
authors.forename: John C
authors.initials: JC
authors.lastname: Silbereis
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.forename: Charlotte C
authors.initials: CC
authors.lastname: Bruce
authors.forename: Jose J
authors.initials: JJ
authors.lastname: Otero
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.forename: Roel
authors.initials: R
authors.lastname: Nusse
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
mesh_terms: D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D060466:Axin Protein; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001930:Brain Injuries / Q000209:etiology / Q000378:metabolism* / Q000628:therapy*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000166:cytology; D003337:Corpus Callosum / Q000187:drug effects / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007231:Infant, Newborn; D019394:Ki-67 Antigen / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009103:Multiple Sclerosis / Q000150:complications / Q000473:pathology / Q000628:therapy; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D011180:Postmortem Changes; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D060466:Axin Protein; D051792:Basic Helix-Loop-Helix Proteins; D003598:Cytoskeletal Proteins; D006575:Heterocyclic Compounds, 3-Ring; D019394:Ki-67 Antigen; D008244:Lysophosphatidylcholines; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D051153:Wnt Proteins; D051176:beta Catenin; D001616:beta-Galactosidase; C491761:AXIN2 protein, human; C405708:OLIG2 protein, human; C544261:XAV939