Academic journal article Genetics

Axon Response to Guidance Cues Is Stimulated by Acetylcholine in Caenorhabditis Elegans

Academic journal article Genetics

Axon Response to Guidance Cues Is Stimulated by Acetylcholine in Caenorhabditis Elegans

Article excerpt

ABSTRACT Gradients of acetylcholine can stimulate growth cone turning when applied to neurons grown in culture, and it has been suggested that acetylcholine could act as a guidance cue. However, the role acetylcholine plays in directing axon migrations in vivo is not clear. Here, we show that acetylcholine positively regulates signaling pathways that mediate axon responses to guidance cues in Caenorhabditis elegans. Mutations that disrupt acetylcholine synthesis, transportation, and secretion affect circumferential axon guidance of the AVM neuron and in these mutants exogenously supplied acetylcholine improves AVM circumferential axon guidance. These effects are not observed for the circumferential guidance of the DD and VD motor neuron axons, which are neighbors of the AVM axon. Circumferential guidance is directed by the UNC-6 (netrin) and SLT-1 (slit) extracellular cues, and exogenously supplied acetylcholine can improve AVM axon guidance in mutants when either UNC-6- or SLT-1-induced signaling is disrupted, but not when both signaling pathways are perturbed. Not in any of the mutants does exogenously supplied acetylcholine improve DD and VD axon guidance. The ability of acetylcholine to enhance AVM axon guidance only in the presence of either UNC-6 or SLT-1 indicates that acetylcholine potentiates UNC-6 and SLT-1 guidance activity, rather than acting itself as a guidance cue. Together, our results show that for specific neurons acetylcholine plays an important role in vivo as a modulator of axon responses to guidance cues.

CELLS secrete molecules that help guide axon growth cone migrations. In Caenorhabditis elegans, UNC-6 (netrin) and SLT-1 (slit) are secreted guidance cues and are ligands for the UNC-40 (DCC) and SAX-3 (Robo) receptors, which are present at the surface of the migrating axons (Hedgecock et al. 1990; Serafini et al. 1994; Chan et al. 1996; Keino-Masu et al. 1996; Wadsworth et al. 1996; Zallen et al. 1998; Brose et al. 1999; Hao et al. 2001). During nervous system development, different cells can spatially and temporally express a guidance cue to create dynamic patterns (Wadsworth et al. 1996). This expression can provide pathway and long-range signals, allowing for complex axon trajectories during the formation of neural circuits (Wadsworth and Hedgecock 1996). Additional extracellular guidance cues and other factors can further modify growth cone responses and alter trajectories. How multiple extracellular molecules together direct growth cone migrations is still not well understood.

Acetylcholine is best known as a molecule secreted at synapses, where it acts as a neurotransmitter. However, there is evidence to suggest that during early development acetylcholine has other roles, including the role of an axon guidance cue (Ruediger and Bolz 2007). Studies using chick, Xenopus, and Drospophila embryonic neurons indicate that acetylcholine is also secreted before synapses form (Hume et al. 1983; Young and Poo 1983; Yao et al. 2000). During this time, acetylcholine might influence different aspects of nervous system development, including the process of axon guidance. Moreover, under cell culture conditions, defined extracellular gradients of acetylcholine elicit turning responses from neuronal growth cones (Zheng et al. 1994; Kuffler 1996). A developmental role for acetylcholine in axon pathfinding in vivo was revealed when it was shown that Drosophila photoreceptor axons do not properly project to their targets when acetylcholine synthesis or metabolism is altered or eliminated (Yang and Kunes 2004).

In this article, we present evidence that extracellular acetylcholine is required for a migrating axon to properly respond to guidance cues in vivo. In C. elegans, the ventral axon migration of the AVM neuron is directed by the UNC-6 and SLT-1 guidance cues through signaling mediated by the UNC-40 and SAX-3 receptors (Hedgecock et al. 1990; Wadsworth et al. 1996; Hao et al. 2001; Yu et al. …

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