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The Journal of Neuroscience, March 19, 2008, 28(12):3246-3256; doi:10.1523/JNEUROSCI.5446-07.2008

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Cellular/Molecular
Voltage-Gated Na⁺ Channel β1 Subunit-Mediated Neurite Outgrowth Requires Fyn Kinase and Contributes to Postnatal CNS Development In Vivo

William J. Brackenbury,¹ Tigwa H. Davis,¹ Chunling Chen,¹ Emily A. Slat,¹ Matthew J. Detrow,¹ Travis L. Dickendesher,¹ Barbara Ranscht,² and Lori L. Isom¹

¹Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109-0632, and ²Burnham Institute for Medical Research, La Jolla, California 92037

Correspondence should be addressed to Dr. Lori L. Isom, Department of Pharmacology, 1150 West Medical Center Drive, 1301 MSRB III, Ann Arbor, MI 48109-0632. Email: lisom{at}umich.edu

Voltage-gated Na⁺ channel β1 subunits are multifunctional, participating in channel modulation and cell adhesion in 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 in Fyn and contactin (Cntn) null CGNs. β1 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 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, Scn1b null 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 of Scn1b null 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 β1 in 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.

Key words: voltage-gated Na⁺ channel; neurite outgrowth; auxiliary subunit; cell adhesion molecule; contactin; fyn kinase

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Received June 20, 2007; revised Jan. 30, 2008; accepted Feb. 12, 2008.

Correspondence should be addressed to Dr. Lori L. Isom, Department of Pharmacology, 1150 West Medical Center Drive, 1301 MSRB III, Ann Arbor, MI 48109-0632. Email: lisom{at}umich.edu

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