title: Complement protein C1q modulates neurite outgrowth in vitro and spinal cord axon regeneration in vivo.
abstract: Traumatic injury to CNS fiber tracts is accompanied by failure of severed axons to regenerate and results in lifelong functional deficits. The inflammatory response to CNS trauma is mediated by a diverse set of cells and proteins with varied, overlapping, and opposing effects on histological and behavioral recovery. Importantly, the contribution of individual inflammatory complement proteins to spinal cord injury (SCI) pathology is not well understood. Although the presence of complement components increases after SCI in association with axons and myelin, it is unknown whether complement proteins affect axon growth or regeneration. We report a novel role for complement C1q in neurite outgrowth in vitro and axon regrowth after SCI. In culture, C1q increased neurite length on myelin. Protein and molecular assays revealed that C1q interacts directly with myelin associated glycoprotein (MAG) in myelin, resulting in reduced activation of growth inhibitory signaling in neurons. In agreement with a C1q-outgrowth-enhancing mechanism in which C1q binding to MAG reduces MAG signaling to neurons, complement C1q blocked both the growth inhibitory and repulsive turning effects of MAG in vitro. Furthermore, C1q KO mice demonstrated increased sensory axon turning within the spinal cord lesion after SCI with peripheral conditioning injury, consistent with C1q-mediated neutralization of MAG. Finally, we present data that extend the role for C1q in axon growth and guidance to include the sprouting patterns of descending corticospinal tract axons into spinal gray matter after dorsal column transection SCI.
authors.affiliation: Sue and Bill Gross Stem Cell Center, Institute for Memory Impairments and Neurological Disorders, Department of Anatomy and Neurobiology, and.
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Peterson
authors.affiliation: Sue and Bill Gross Stem Cell Center, Institute for Memory Impairments and Neurological Disorders.
authors.forename: Hal X
authors.initials: HX
authors.lastname: Nguyen
authors.affiliation: Sue and Bill Gross Stem Cell Center, Institute for Memory Impairments and Neurological Disorders.
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Mendez
authors.affiliation: Sue and Bill Gross Stem Cell Center, Institute for Memory Impairments and Neurological Disorders, Department of Anatomy and Neurobiology, and Department of Physical Medicine and Rehabilitation, University of California, Irvine, California 92697 aja@uci.edu.
authors.forename: Aileen J
authors.identifier: http://orcid.org/0000-0002-8203-8891
authors.initials: AJ
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D001369:Axons / Q000187:drug effects*; D002478:Cells, Cultured; D015922:Complement C1q / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000187:drug effects / Q000502:physiology; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology
chemical_list: D019922:GAP-43 Protein; D018992:Myelin-Associated Glycoprotein; D015922:Complement C1q; D000242:Cyclic AMP; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: C1q; complement; inflammation; regeneration; spinal cord injury; sprouting