Voltage-gated Na+ channel beta 1 subunit-mediated neurite outgrowth requires fyn kinase and contributes to postnatal CNS development in vivo

William J. Brackenbury, Tigwa H. Davis, Chunling Chen, Emily A. Slat, Matthew J. Detrow, Travis L. Dickendesher, Barbara Ranscht, Lori L. Isom

Research output: Contribution to journalArticlepeer-review

Abstract

Voltage-gated Na+ channel beta 1 subunits are multifunctional, participating in channel modulation and cell adhesion in vitro. We previously demonstrated that beta 1 promotes neurite outgrowth of cultured cerebellar granule neurons (CGNs) via homophilic adhesion. Both lipid raft-associated kinases and nonraft fibroblast growth factor (FGF) receptors are implicated in cell adhesion molecule-mediated neurite extension. In the present study, we reveal that beta 1-mediated neurite outgrowth is abrogated in Fyn and contactin (Cntn) null CGNs. beta 1 protein levels are unchanged in Fyn null brains, whereas levels are significantly reduced in Cntn null brain lysates. FGF or EGF (epidermal growth factor) receptor kinase inhibitors have no effect on beta 1-mediated neurite extension. These results suggest that beta 1-mediated neurite outgrowth occurs through a lipid raft signaling mechanism that requires the presence of both fyn kinase and contactin. In vivo, Scn1b null mice show defective CGN axon extension and fasciculation indicating that beta 1 plays a role in cerebellar microorganization. In addition, we find that axonal pathfinding and fasciculation are abnormal in corticospinal tracts of Scn1b null mice consistent with the suggestion that beta 1 may have widespread effects on postnatal neuronal development. These data are the first to demonstrate a cell-adhesive role for beta 1 in vivo. We conclude that voltage-gated Na+ channel beta 1 subunits signal via multiple pathways on multiple timescales and play important roles in the postnatal development of the CNS.

Original languageEnglish
Pages (from-to)3246-3256
Number of pages11
JournalJournal of neuroscience
Volume28
Issue number12
DOIs
Publication statusPublished - 19 Mar 2008

Keywords

  • voltage-gated Na+ channel
  • neurite outgrowth
  • auxiliary subunit
  • cell adhesion molecule
  • contactin
  • fyn kinase
  • CELL-ADHESION MOLECULE
  • RHYTHMICALLY ACTIVE NEURONS
  • FEBRILE SEIZURES PLUS
  • SODIUM-CHANNEL
  • BETA-1 SUBUNITS
  • LIPID RAFTS
  • IMMUNOGLOBULIN SUPERFAMILY
  • GENERALIZED EPILEPSY
  • ION CHANNELS
  • FUNCTIONAL EXPRESSION

Cite this