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PMID:18354028

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Citation

Brackenbury, WJ, Davis, TH, Chen, C, Slat, EA, Detrow, MJ, Dickendesher, TL, Ranscht, B and Isom, LL (2008) Voltage-gated Na+ channel beta1 subunit-mediated neurite outgrowth requires Fyn kinase and contributes to postnatal CNS development in vivo. J. Neurosci. 28:3246-56

Abstract

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.

Links

PubMed Online version:10.1523/JNEUROSCI.5446-07.2008

Keywords

Amino Acids/diagnostic use; Analysis of Variance; Animals; Animals, Newborn; Bromodeoxyuridine/metabolism; Cell Proliferation; Cells, Cultured; Central Nervous System/cytology; Central Nervous System/growth & development; Keratinocytes/physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurites/physiology; Neurons/cytology; Neurons/physiology; Proto-Oncogene Proteins c-fyn/deficiency; Proto-Oncogene Proteins c-fyn/physiology; Sodium Channels/deficiency; Sodium Channels/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:CNTN1

acts_upstream_of_or_within

GO:0021549: cerebellum development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3043422

P

  • results_in_development_of:(EMAPA:17787)

Seeded From UniProt

complete

MOUSE:CNTN1

acts_upstream_of_or_within

GO:0010976: positive regulation of neuron projection development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98247

P

Seeded From UniProt

complete

MOUSE:SCN1B

acts_upstream_of_or_within

GO:0021966: corticospinal neuron axon guidance

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3043422

P

  • occurs_in:(EMAPA:16470)

Seeded From UniProt

complete

MOUSE:SCN1B

acts_upstream_of_or_within

GO:0007411: axon guidance

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3043422

P

  • occurs_in:(EMAPA:17787)

Seeded From UniProt

complete

MOUSE:SCN1B

acts_upstream_of_or_within

GO:0010976: positive regulation of neuron projection development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:105980
MGI:MGI:95602

P

  • regulates_o_occurs_in:(EMAPA:17787)
  • regulates_o_occurs_in:(CL:0001031)

Seeded From UniProt

complete

MOUSE:FYN

acts_upstream_of_or_within

GO:0010976: positive regulation of neuron projection development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:98247

P

  • regulates_o_occurs_in:(EMAPA:17787)
  • regulates_o_occurs_in:(CL:0001031)

Seeded From UniProt

complete


See also

References

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