Netrin signaling shapes sexually dimorphic neurite branching of a sex-shared interneuron in C. elegans

Abstract

Sexually dimorphic behaviors arise from underlying differences in neural circuit architecture between the sexes, yet the molecular mechanisms that establish these structural differences remain poorly understood. In Caenorhabditis elegans, the sex-shared interneuron AVG exhibits sexually dimorphic synaptic connectivity, offering a model for investigating the development of sexually dimorphic neuronal morphology. Here, we identified that AVG displays male-specific neurite branching and demonstrated that the conserved axon guidance cue UNC-6/Netrin and its receptor UNC-40/DCC are essential for this structural remodeling. Cell-specific manipulation of sexual identity revealed that male identity confers branching competence to AVG. Loss of UNC-6 or UNC-40 abolished branch formation, whereas loss of the alternate Netrin receptor UNC-5/Unc5 had no detectable effect. Cell-specific rescue experiments showed that UNC-40 functions in AVG through its UNC-6 binding domains. Furthermore, genetic ablation of the male-specific presynaptic neuron PCA, which expresses unc-6, diminished AVG branch length, establishing PCA as a candidate local source of UNC-6. Together, our findings support a model in which presynaptic UNC-6/Netrin cues from male-specific neurons promote dimorphic neurite branching in sex-shared neurons, illustrating how evolutionarily conserved signaling molecules are redeployed during sexual maturation to sculpt sex-specific neural circuits.