Neuronal Target Identification Requires AHA-1-Mediated Fine-Tuning of Wnt Signaling in C. elegans

Abstract

Electrical synaptic transmission through gap junctions is a vital mode of intercellular communication in the nervous system. The mechanism by which reciprocal target cells find each other during the formation of gap junctions, however, is poorly understood. Here we show that gap junctions are formed between BDU interneurons and PLM mechanoreceptors in C. elegans and the connectivity of BDU with PLM is influenced by Wnt signaling. We further identified two PAS-bHLH family transcription factors, AHA-1 and AHR-1, which function cell-autonomously within BDU and PLM to facilitate the target identification process. aha-1 and ahr-1 act genetically upstream of cam-1. CAM-1, a membrane-bound receptor tyrosine kinase, is present on both BDU and PLM cells and likely serves as a Wnt antagonist. By binding to a cis-regulatory element in the cam-1 promoter, AHA-1 enhances cam-1 transcription. Our study reveals a Wnt-dependent fine-tuning mechanism that is crucial for mutual target cell identification during the formation of gap junction connections.

Aryl hydrocarbon receptor (AHR) in the cnidarian Nematostella vectensis: comparative expression, protein interactions, and ligand binding

“…Previous research comparing the function of AHR orthologs in protostomes and deuterostomes has suggested that a potential conserved role for AHR is in the development and specification of neuronal sensory systems (e.g., Huang et al 2004; Kim et al 2006; Qin and Powell-Coffman 2004; Smith et al 2013; Zhang et al 2013). The cnidarians represent an early diverging phylum containing true neurons that are diffusely organized in what is traditionally termed a nerve net.…”

“…AHR-1 is expressed in a specific subset of neurons (28 out of the 302 C. elegans neurons), including touch receptor neurons, neurons that contact the pseudocoelomic fluid, and neurons in the pharynx (Qin and Powell-Coffman 2004). AHR-1 loss-of-function mutants exhibit altered neuronal differentiation leading to defective migration and morphology of touch receptor neurons and GABAergic motor neurons (Huang et al 2004; Qin and Powell-Coffman 2004; Smith et al 2013; Zhang et al 2013). In addition to its developmental roles in C. elegans , AHR-1 also continues to function in adult neurons, playing an important role in determining social feeding behavior through regulation of soluble guanylate cyclases (Qin et al 2006).…”

Diversity as opportunity: Insights from 600 million years of AHR evolution

“…Loss of AHR-1 function results in defective neuronal migration and axonal pathfinding, altered touch neuron fate, and changes in locomotor and social feeding behaviors [35–37]. The role of AHR-1 in neuronal development requires ARNT (AHA-1) [35,36] and may involve regulation of wnt signaling [38]. In addition to its roles in development, AHR-1 appears to have an ongoing role in regulating the expression of oxygen-sensing guanylate cyclases involved in the control of feeding behavior [39,40].…”

“…Conceivably, shared features of AHR function may be more readily identified at the level of molecular interactions such as those involving gene regulation or protein-protein interactions. For example, interaction with wnt signaling appears to be a shared, and thus possibly evolutionarily conserved, feature of vertebrate and invertebrate AHRs [38,110–113]. A comparative analysis of gene regulatory networks involving AHR in a variety of vertebrate and invertebrate model systems could illuminate additional ancient molecular interactions [40,114–116].…”

RPM-1 regulates axon termination by affecting growth cone collapse and microtubule stability

“…Recently, it has been shown the terminated PLM axon tip contains electrical synapses ( Fig. 1B) (Zhang et al, 2013). It remains uncertain whether the axon termination program impacts electrical synapse formation.…”