Voltage-Gated Na+Channel β1 Subunit-Mediated Neurite Outgrowth Requires Fyn Kinase and Contributes to Postnatal CNS DevelopmentIn Vivo

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Abstract
Voltage-gated Na+channel β1 subunits are multifunctional, participating in channel modulation and cell adhesionin vitro. We previously demonstrated that β1 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 β1-mediated neurite outgrowth is abrogated inFynand contactin (Cntn) null CGNs. β1 protein levels are unchanged inFynnull brains, whereas levels are significantly reduced inCntnnull brain lysates. FGF or EGF (epidermal growth factor) receptor kinase inhibitors have no effect on β1-mediated neurite extension. These results suggest that β1-mediated neurite outgrowth occurs through a lipid raft signaling mechanism that requires the presence of both fyn kinase and contactin.In vivo,Scn1bnull mice show defective CGN axon extension and fasciculation indicating that β1 plays a role in cerebellar microorganization. In addition, we find that axonal pathfinding and fasciculation are abnormal in corticospinal tracts ofScn1bnull mice consistent with the suggestion that β1 may have widespread effects on postnatal neuronal development. These data are the first to demonstrate a cell-adhesive role for β1in vivo. We conclude that voltage-gated Na+channel β1 subunits signal via multiple pathways on multiple timescales and play important roles in the postnatal development of the CNS.

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