Spatiotemporal ablation of myelinating glia-specific neurofascin (NfascNF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains

Anilkumar M. Pillai, Courtney Thaxton, Alaine L. Pribisko, Gang Cheng, Jeffrey L. Dupree, Manzoor A. Bhat

Research output: Contribution to journalArticlepeer-review

123 Scopus citations

Abstract

The evolutionary demand for rapid nerve impulse conduction led to the process of myelination-dependent organization of axons into distinct molecular domains. These domains include the node of Ranvier flanked by highly specialized paranodal domains where myelin loops and axolemma orchestrate the axoglial septate junctions. These junctions are formed by interactions between a glial isoform of neurofascin (NfascNF155) and axonal Caspr and Cont. Here we report the generation of myelinating glia-specific NfascNF155 null mouse mutants. These mice exhibit severe ataxia, motor paresis, and death before the third postnatal week. In the absence of glial NfascNF155, paranodal axoglial junctions fail to form, axonal domains fail to segregate, and myelinated axons undergo degeneration. Electrophysiological measurements of peripheral nerves from NfascNF155 mutants revealed dramatic reductions in nerve conduction velocities. By using inducible PLP-CreER recombinase to ablate NfascNF155 in adult myelinating glia, we demonstrate that paranodal axoglial junctions disorganize gradually as the levels of NfascNF155 protein at the paranodes begin to drop. This coincides with the loss of the paranodal region and concomitant disorganization of the axonal domains. Our results provide the first direct evidence that the maintenance of axonal domains requires the fence function of the paranodal axoglial junctions. Together, our studies establish a central role for paranodal axoglial junctions in both the organization and the maintenance of axonal domains in myelinated axons.

Original languageEnglish (US)
Pages (from-to)1773-1793
Number of pages21
JournalJournal of Neuroscience Research
Volume87
Issue number8
DOIs
StatePublished - 2009
Externally publishedYes

Keywords

  • Axoglial junctions
  • Axonal domains
  • Myelin
  • Myelinated axons
  • Paranodes

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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