title: Abrogation of β-catenin signaling in oligodendrocyte precursor cells reduces glial scarring and promotes axon regeneration after CNS injury.
abstract: When the brain or spinal cord is injured, glial cells in the damaged area undergo complex morphological and physiological changes resulting in the formation of the glial scar. This scar contains reactive astrocytes, activated microglia, macrophages and other myeloid cells, meningeal cells, proliferating oligodendrocyte precursor cells (OPCs), and a dense extracellular matrix. Whether the scar is beneficial or detrimental to recovery remains controversial. In the acute phase of recovery, scar-forming astrocytes limit the invasion of leukocytes and macrophages, but in the subacute and chronic phases of injury the glial scar is a physical and biochemical barrier to axonal regrowth. The signals that initiate the formation of the glial scar are unknown. Both canonical and noncanonical signaling Wnts are increased after spinal cord injury (SCI). Because Wnts are important regulators of OPC and oligodendrocyte development, we examined the role of canonical Wnt signaling in the glial reactions to CNS injury. In adult female mice carrying an OPC-specific conditionally deleted β-catenin gene, there is reduced proliferation of OPCs after SCI, reduced accumulation of activated microglia/macrophages, and reduced astrocyte hypertrophy. Using an infraorbital optic nerve crush injury, we show that reducing β-catenin-dependent signaling in OPCs creates an environment that is permissive to axonal regeneration. Viral-induced expression of Wnt3a in the normal adult mouse spinal cord induces an injury-like response in glia. Thus canonical Wnt signaling is both necessary and sufficient to induce injury responses among glial cells. These data suggest that targeting Wnt expression after SCI may have therapeutic potential in promoting axon regeneration.
authors: Program in Neuroscience and Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, New York 11794.
authors: Justin P
authors: JP
authors: Rodriguez
authors: Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, New York 11794.
authors: Michael
authors: M
authors: Coulter
authors: Department of Developmental and Cell Biology, University of California, Irvine, California 92697, and.
authors: Jill
authors: J
authors: Miotke
authors: Department of Developmental and Cell Biology, University of California, Irvine, California 92697, and.
authors: Ronald L
authors: RL
authors: Meyer
authors: Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794.
authors: Ken-Ichi
authors: http://orcid.org/0000-0001-9657-9966
authors: K
authors: Takemaru
authors: Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, New York 11794, Joel.Levine@stonybrook.edu.
authors: Joel M
authors: JM
authors: Levine
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002493:Central Nervous System Diseases / Q000503:physiopathology* / Q000628:therapy; D002921:Cicatrix / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000502:physiology*; D009836:Oligodendroglia / Q000378:metabolism*; D009901:Optic Nerve Diseases / Q000473:pathology / Q000503:physiopathology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics*; D013629:Tamoxifen / Q000494:pharmacology; D051176:beta Catenin / Q000172:deficiency*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D008164:Luminescent Proteins; D020845:Selective Estrogen Receptor Modulators; D051176:beta Catenin; D013629:Tamoxifen; D020796:Receptor, Platelet-Derived Growth Factor alpha; D001973:Bromodeoxyuridine
keywords: Wnt; glia; inflammation; repair