Neurofascin assembles a specialized extracellular matrix at the axon initial segment

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  • Kristian L. Hedstrom
    1Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06032
  • Xiaorong Xu
    2Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, NY 14642
  • Yasuhiro Ogawa
    1Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06032
  • Renato Frischknecht
    3Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany
  • Constanze I. Seidenbecher
    3Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany
  • Peter Shrager
    2Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, NY 14642
  • Matthew N. Rasband
    1Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06032

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<jats:p>Action potential initiation and propagation requires clustered Na+ (voltage-gated Na+ [Nav]) channels at axon initial segments (AIS) and nodes of Ranvier. In addition to ion channels, these domains are characterized by cell adhesion molecules (CAMs; neurofascin-186 [NF-186] and neuron glia–related CAM [NrCAM]), cytoskeletal proteins (ankyrinG and βIV spectrin), and the extracellular chondroitin-sulfate proteoglycan brevican. Schwann cells initiate peripheral nervous system node formation by clustering NF-186, which then recruits ankyrinG and Nav channels. However, AIS assembly of this protein complex does not require glial contact. To determine the AIS assembly mechanism, we silenced expression of AIS proteins by RNA interference. AnkyrinG knockdown prevented AIS localization of all other AIS proteins. Loss of NF-186, NrCAM, Nav channels, or βIV spectrin did not affect other neuronal AIS proteins. However, loss of NF-186 blocked assembly of the brevican-based AIS extracellular matrix, and NF-186 overexpression caused somatodendritic brevican clustering. Thus, NF-186 assembles and links the specialized brevican-containing AIS extracellular matrix to the intracellular cytoskeleton.</jats:p>

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