Sex-specific neurons instruct sexually dimorphic neurite branching via Netrin signaling in Caenorhabditis elegans

Abstract

Animals often exhibit sexually dimorphic behavior in mating, learning, and decision-making. These sexual dimorphisms arise due to sex differences in the structure and function of neural circuits, but how sexually dimorphic neural circuits are established remains less understood. In the nematode C. elegans, both males and hermaphrodites possess a set of sex-shared neurons with sexually dimorphic features that contribute to the observed sex differences in neural connectivity. Here, we focused on the motor neuron preanal cell body dorsal axon B (PDB) to investigate the molecular mechanism underlying sexually dimorphic neurite branching. The PDB neuron exhibits extensive neurite branches near the cell body in males but not in hermaphrodites. By manipulating the sexual identity of PDB neurons, we discovered that neurite branching is influenced by both cell-autonomous and non-autonomous factors. We found that the UNC-6/Netrin signaling is crucial for the elaborate PDB neurite branching in males. Specifically, UNC-6/Netrin, expressed in a set of male-specific neurons, induces the formation of PDB neurite branches. The cognate receptor UNC-40/deleted in colorectal cancer (DCC), located in the PDB neurites, plays a role in mediating neurite branching in response to the UNC-6/Netrin cue. Furthermore, we show that males with aberrant PDB neurite branches exhibit defects in male mating behavior, particularly in coordinating movements required for successful mating. Our findings provide insights into the establishment of sexually dimorphic neural circuits, demonstrating how an evolutionarily conserved molecular cue and its receptor can be utilized in this process. © 2025 Elsevier Inc.