The anti-invasive compound motuporamine C is a robust stimulator of neuronal growth cone collapse.
Neuronal outgrowth is a fundamental process for normal development of the nervous system. Despite recent advances, the molecular mechanisms governing neuronal motility are still poorly understood. To provide insight into the intracellular signaling mechanisms required for neuronal outgrowth, we have characterized the effects of a compound previously identified for its anti-motility effects on transformed cells. We show that this compound, motuporamine C, acts as a robust inhibitor of chick neurite outgrowth in a dose-dependent fashion. Furthermore, in the presence of motuporamine C, growth cone collapse is observed, followed by neurite retraction. After removal, growth cones re-extend lamellipodial and filopodial processes and re-establish motility. Neurons exposed to motuporamine C exhibit a significant upregulation of active Rho-GTP. Additionally, effector-blocking experiments using Rho and Rho-associated kinase inhibitors indicate that the Rho pathway plays a critical role in motuporamine C-mediated growth cone collapse. Thus, we have characterized a novel anti-motility compound that has a robust inhibitory effect on neuronal outgrowth and involves signaling through the Rho-Rho kinase collapse pathway. Due to these robust effects, motuporamine C may serve as a valuable tool in further examining the intracellular mechanisms associated with growth cone motility.
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KC
Department of Cellular and Physiological Sciences, 2350 Health Sciences Mall, University of British Columbia, Vancouver, Canada. kento@interchange.ubc.ca
Loh
K T
KT
Roskelley
C D
CD
Andersen
R J
RJ
O'Connor
T P
TP
D000470:Alkaloids / Q000494:pharmacology*; D000577:Amides / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D020439:Growth Cones / Q000187:drug effects*; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D018715:Microscopy, Video / Q000379:methods; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009924:Organ Culture Techniques; D011725:Pyridines / Q000494:pharmacology; D013997:Time Factors; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000470:Alkaloids; D000577:Amides; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D011725:Pyridines; C409085:motuporamine C; C108830:Y 27632; D020741:rho GTP-Binding Proteins