Rotenone inhibits axonogenesis via an Lfc/RhoA/ROCK pathway in cultured hippocampal neurons.
Rotenone, a broad-spectrum insecticide, piscicide and pesticide, produces a complete and selective suppression of axonogenesis in cultured hippocampal neurons. This effect is associated with an inhibition of actin dynamics through activation of Ras homology member A (RhoA) activity. However, the upstream signaling mechanisms involved in rotenone-induced RhoA activation were unknown. We hypothesized that rotenone might inhibit axon growth by the activation of RhoA/ROCK pathway because of the changes in microtubule (MT) dynamics and the concomitant release of Lfc, a MT-associated Guanine Nucleotide Exchange Factor (GEF) for RhoA. In this study, we demonstrate that rotenone decreases MT stability in morphologically unpolarized neurons. Taxol (3 nM), a drug that stabilizes MT, attenuates the inhibitory effect of rotenone (0.1 μM) on axon formation. Radiometric Forster Resonance Energy Transfer, revealed that this effect is associated with inhibition of rotenone-induced RhoA and ROCK activation. Interestingly, silencing of Lfc, but not of the RhoA GEF ArhGEF1, prevents the inhibitory effect of rotenone on axon formation. Our results suggest that rotenone-induced MT de-stabilization releases Lfc from MT thereby promoting RhoA and ROCK activities and the consequent inhibition of axon growth. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.
['Bisbal|Mariano|M|', 'Remedi|Mónica|M|', 'Quassollo|Gonzalo|G|', 'Cáceres|Alfredo|A|', 'Sanchez|Mónica|M|']
D000818:Animals D002478:Cells, Cultured D004622:Embryo, Mammalian D005260:Female D020662:Guanine Nucleotide Exchange Factors D006624:Hippocampus D007306:Insecticides D055495:Neurogenesis D009474:Neurons D010766:Phosphorylation D011247:Pregnancy D051381:Rats D012402:Rotenone D015398:Signal Transduction D014161:Transduction, Genetic D014404:Tubulin D020741:rho GTP-Binding Proteins D054460:rho-Associated Kinases D016875:tau Proteins
rotenone Lfc RhoA ROCK neurons axon neurotoxicity