Voltage-gated Na+ channel beta1 subunit-mediated neurite outgrowth requires Fyn kinase and contributes to postnatal CNS development in vivo.
Voltage-gated Na(+) channel beta1 subunits are multifunctional, participating in channel modulation and cell adhesion in vitro. We previously demonstrated that beta1 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 beta1-mediated neurite outgrowth is abrogated in Fyn and contactin (Cntn) null CGNs. beta1 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 beta1-mediated neurite extension. These results suggest that beta1-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 beta1 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 beta1 may have widespread effects on postnatal neuronal development. These data are the first to demonstrate a cell-adhesive role for beta1 in vivo. We conclude that voltage-gated Na(+) channel beta1 subunits signal via multiple pathways on multiple timescales and play important roles in the postnatal development of the CNS.
Brackenbury
William J
WJ
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109-0632, USA.
Davis
Tigwa H
TH
Chen
Chunling
C
Slat
Emily A
EA
Detrow
Matthew J
MJ
Dickendesher
Travis L
TL
Ranscht
Barbara
B
Isom
Lori L
LL
D000596:Amino Acids; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000254:growth & development*; D015603:Keratinocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016501:Neurites / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn / Q000172:deficiency / Q000502:physiology*; D015222:Sodium Channels / Q000172:deficiency / Q000502:physiology*; D062547:Voltage-Gated Sodium Channel beta-1 Subunit
D000596:Amino Acids; C524974:Scn1b protein, mouse; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; C098463:dolaisoleucine; D051076:Proto-Oncogene Proteins c-fyn; D001973:Bromodeoxyuridine