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1. Parallel states of pathological Wnt signaling in neonatal brain injury and colon cancer.

Author

Fancy SP, Harrington EP, Baranzini SE, Silbereis JC, Shiow LR, Yuen TJ, Huang EJ, Lomvardas S, and Rowitch DH

Subjects
Adenomatous Polyposis Coli Protein genetics, Adenomatous Polyposis Coli Protein metabolism, Animals, Biomarkers metabolism, Brain Injuries pathology, Cell Differentiation, Colonic Neoplasms pathology, Female, Gene Expression Regulation physiology, Genetic Association Studies, Humans, Infant, Newborn, Infant, Newborn, Diseases, Mice, Mice, Transgenic, Oligodendroglia metabolism, Random Allocation, Up-Regulation, Wnt Proteins genetics, Wnt Proteins metabolism, Wnt Signaling Pathway genetics, Brain Injuries metabolism, Brain Injuries physiopathology, Colonic Neoplasms physiopathology, Hypoxia metabolism, Leukoencephalopathies metabolism, Oligodendroglia physiology, Wnt Proteins physiology, Wnt Signaling Pathway physiology
Abstract

In colon cancer, mutation of the Wnt repressor APC (encoding adenomatous polyposis coli) leads to a state of aberrant and unrestricted high-activity signaling. However, the relevance of high Wnt tone in non-genetic human disease is unknown. Here we demonstrate that distinct functional states of Wnt activity determine oligodendrocyte precursor cell (OPC) differentiation and myelination. Mouse OPCs with genetic Wnt dysregulation (high tone) express multiple genes in common with colon cancer, including Lef1, Sp5, Ets2, Rnf43 and Dusp4. Surprisingly, we found that OPCs in lesions of hypoxic human neonatal white matter injury upregulated markers of high Wnt activity and lacked expression of APC. We also found that lack of Wnt repressor tone promoted permanent white matter injury after mild hypoxic insult. These findings suggest a state of pathological high-activity Wnt signaling in human disease tissues that lack predisposing genetic mutation.

Published
2014
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2. Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination.

Author

Fancy SP, Harrington EP, Yuen TJ, Silbereis JC, Zhao C, Baranzini SE, Bruce CC, Otero JJ, Huang EJ, Nusse R, Franklin RJ, and Rowitch DH

Subjects
Adult, Animals, Animals, Newborn, Axin Protein, Basic Helix-Loop-Helix Transcription Factors genetics, Brain Injuries etiology, 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, Demyelinating Diseases chemically induced, Demyelinating Diseases pathology, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Gene Expression Regulation genetics, 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, 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 therapeutic use, Myelin Sheath drug effects, Myelin Sheath pathology, Myelin Sheath ultrastructure, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neurons drug effects, Oligodendrocyte Transcription Factor 2, Oligodendroglia drug effects, Oligodendroglia physiology, Organ Culture Techniques, Postmortem Changes, Spinal Cord drug effects, Spinal Cord physiology, Stem Cells drug effects, Wnt Proteins genetics, Wnt Proteins metabolism, beta Catenin genetics, beta Catenin metabolism, beta-Galactosidase genetics, beta-Galactosidase metabolism, Brain Injuries metabolism, Brain Injuries therapy, Cytoskeletal Proteins metabolism, Gene Expression Regulation physiology, Myelin Proteins metabolism
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.

Published
2011
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