title: Reassembly of Excitable Domains after CNS Axon Regeneration.
abstract: Action potential initiation and propagation in myelinated axons require ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Disruption of these domains after injury impairs nervous system function. Traditionally, injured CNS axons are considered refractory to regeneration, but some recent approaches challenge this view by showing robust long-distance regeneration. However, whether these approaches allow remyelination and promote the reestablishment of AIS and nodes of Ranvier is unknown. Using mouse optic nerve crush as a model for CNS traumatic injury, we performed a detailed analysis of AIS and node disruption after nerve crush. We found significant disruption of AIS and loss of nodes within days of the crush, and complete loss of nodes 1 week after injury. Genetic deletion of the tumor suppressor phosphatase and tensin homolog (Pten) in retinal ganglion cells (RGCs), coupled with stimulation of RGCs by inflammation and cAMP, dramatically enhanced regeneration. With this treatment, we found significant reestablishment of RGC AIS, remyelination, and even reassembly of nodes in regions proximal, within, and distal to the crush site. Remyelination began near the retina, progressed distally, and was confirmed by electron microscopy. Although axons grew rapidly, remyelination and nodal ion channel clustering was much slower. Finally, genetic deletion of ankyrinG from RGCs to block AIS reassembly did not affect axon regeneration, indicating that preservation of neuronal polarity is not required for axon regeneration. Together, our results demonstrate, for the first time, that regenerating CNS axons can be remyelinated and reassemble new AIS and nodes of Ranvier.
  
  
  
  We show, for the first time, that regenerated CNS axons have the capacity to both remyelinate and reassemble the axon initial segments and nodes of Ranvier necessary for rapid and efficient action potential propagation.
authors: Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030.
authors: Miguel A
authors: MA
authors: Marin
authors: Boston Children's Hospital and.
authors: Silmara
authors: S
authors: de Lima
authors: Boston Children's Hospital and.
authors: Hui-Ya
authors: 0000-0002-3170-388X
authors: HY
authors: Gilbert
authors: Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109.
authors: Roman J
authors: 0000-0002-2926-3336
authors: RJ
authors: Giger
authors: Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, and.
authors: Larry
authors: 0000-0002-0277-7222
authors: L
authors: Benowitz
authors: Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, rasband@bcm.edu.
authors: Matthew N
authors: 0000-0001-8184-2477
authors: MN
authors: Rasband
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000235:genetics / Q000378:metabolism; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D015816:Cell Adhesion Molecules, Neuronal; D002772:Cholera Toxin / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000378:metabolism; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009901:Optic Nerve Diseases / Q000473:pathology* / Q000503:physiopathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011901:Ranvier's Nodes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D013049:Spectrin / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: C094681:Ank3 protein, mouse; D017487:Ankyrins; D015816:Cell Adhesion Molecules, Neuronal; C491322:Cntnap1 protein, mouse; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C491046:Scn8a protein, mouse; D013049:Spectrin; D049452:Green Fluorescent Proteins; D002772:Cholera Toxin; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: axon; ion channel; myelin; regeneration