RESUMEN
The ability of neurons to regenerate their axons after injury is determined by a balance between cellular pathways that promote and those that inhibit regeneration. In Caenorhabditis elegans, axon regeneration is positively regulated by the c-Jun N-terminal kinase mitogen activated protein kinase pathway, which is activated by growth factor-receptor tyrosine kinase signalling. Here we show that fatty acid amide hydrolase-1, an enzyme involved in the degradation of the endocannabinoid anandamide (arachidonoyl ethanolamide), regulates the axon regeneration response of γ-aminobutyric acid neurons after laser axotomy. Exogenous arachidonoyl ethanolamide inhibits axon regeneration via the Goα subunit GOA-1, which antagonizes the Gqα subunit EGL-30. We further demonstrate that protein kinase C functions downstream of Gqα and activates the MLK-1-MEK-1-KGB-1 c-Jun N-terminal kinase pathway by phosphorylating MLK-1. Our results show that arachidonoyl ethanolamide induction of a G protein signal transduction pathway has a role in the inhibition of post-development axon regeneration.
Asunto(s)
Axones/fisiología , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/enzimología , Endocannabinoides/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Sistema de Señalización de MAP Quinasas , Regeneración Nerviosa/fisiología , Proteínas Tirosina Quinasas/metabolismo , Amidohidrolasas/metabolismo , Secuencia de Aminoácidos , Animales , Ácidos Araquidónicos/metabolismo , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/antagonistas & inhibidores , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/antagonistas & inhibidores , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Genes de Helminto/genética , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Quinasas Quinasa Quinasa PAM/química , Quinasas Quinasa Quinasa PAM/metabolismo , Modelos Biológicos , Datos de Secuencia Molecular , Alcamidas Poliinsaturadas/metabolismoRESUMEN
The ability of neurons to undergo regenerative growth after injury is governed by cell-intrinsic and cell-extrinsic regeneration pathways. These pathways represent potential targets for therapies to enhance regeneration. However, the signaling pathways that orchestrate axon regeneration are not well understood. In Caenorhabditis elegans, the Jun N-terminal kinase (JNK) and p38 MAP kinase (MAPK) pathways are important for axon regeneration. We found that the C. elegans SVH-1 growth factor and its receptor, SVH-2 tyrosine kinase, regulate axon regeneration. Loss of SVH-1-SVH-2 signaling resulted in a substantial defect in the ability of neurons to regenerate, whereas its activation improved regeneration. Furthermore, SVH-1-SVH-2 signaling was initiated extrinsically by a pair of sensory neurons and functioned upstream of the JNK-MAPK pathway. Thus, SVH-1-SVH-2 signaling via activation of the MAPK pathway acts to coordinate neuron regeneration response after axon injury.
