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.
SignificanceHow a limited repertoire of secreted molecules pattern a large number of axon trajectories is an enduring mystery. Both Slit-Robo and Wnt-Ror pathways are involved in proper neurite extension, but whether and how these two signaling pathways are interacted is largely unknown. Here, we found that instead of mediating Slit signaling, Robo could bind and respond to Wnt ligand. By forming a complex with the Ror receptor and Dsh effector, the Robo receptor promotes signal transduction from Wnt to Dsh. The mechanistic link between the Robo receptor and Wnt-Ror-Dsh signaling revealed here will markedly advance our understanding of how guidance molecules interact in space and time to orchestrate the dynamic process of growth cone navigation through a complex cellular environment.
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