Sex-specific control of locomotor behavior by neuronal Arhgef10 in aged Drosophila

Mutations and polymorphisms in the Rho guanine nucleotide exchange factor 10 (ARHGEF10) locus are associated with behavioral and locomotor dysfunctions in humans, including psychiatric disorders and polyneuropathies that show age- and sex-specific prevalence. ARHGEF10 encodes a conserved guanine exchange factor that activates Rho GTPases and has proposed roles in cell migration and adhesion, but the relevant cell types and mechanisms underlying its age- and sex-dependent effects remain unclear. Drosophila darhgef10 gene is the single orthologue of vertebrate ARHGEF10 and its paralogue ARHGEF10L. Here, to gain insight into possible age- and sex-dependent ARHGEF10 neuromuscular functions, we generated darhgef10 knock-out flies and quantified induced walking kinematics with high-speed imaging and coarse spontaneous behaviors-walking, micromovements, and sleep-in open arenas. Mutants of both sexes exhibited abnormal walking kinematics, which worsened with age in females. Cell-type-specific knockdowns indicated these phenotypes arose primarily from neuronal, rather than glial or muscle, requirements. Loss of darhgef10 also caused sexually dimorphic neurodevelopmental and post-adult-onset behavioral effects: females were more susceptible to total darhgef10 reduction, showing decreased wakefulness and speed. In contrast, darhgef10 isoform imbalance-rather than total loss-drove stronger locomotor effects in males, suggesting complex activity regulation. These sexually dimorphic effects were also largely explained by neuronal darhgef10 activity. Accordingly, dArhgef10 expression was detected in the developing nervous system, where motor neuron-targeted knockdown demonstrated a cell-autonomous requirement in establishing adult muscle innervation patterns. ARHGEF10 thus plays an ancient, conserved role in neurons that promotes proper wakefulness and locomotor activity in an age- and sex-dependent manner.