Genetic Control of Neuroendocrine Signaling Underlies Behavioral Diversity in C. elegans

Lee H, Boor SA, Hilbert ZA, Meisel JD, Park J, Wang Y, McKeown R, Fischer SEJ, Andersen EC, Kim DH. Genetic variants that modify neuroendocrine gene expression and foraging behavior of C. elegans. Sci Adv 2024;10(24):eadk9481. doi: 10.1126/sciadv.adk9481.

Background: Behavioral diversity in animals often arises from genetic differences affecting neuronal gene expression, but the specific molecular mechanisms remain unclear. In Caenorhabditis elegans, the neuroendocrine ligand DAF-7, a transforming growth factor–β homolog, modulates foraging and feeding behaviors. Its neuron-specific expression is regulated by bacterial and environmental cues, suggesting that natural variation in daf-7 regulation may underlie behavioral differences across strains.

Hypothesis: This study hypothesized that naturally occurring genetic variants alter neuron-specific expression of the daf-7 gene in C. elegans and thereby contribute to diversity in foraging behavior.

Methods: The authors compared daf-7 expression in ASJ neurons among wild C. elegans strains using a transgenic daf-7p::GFP reporter and mapped causative variants through recombinant inbred lines and near-isogenic lines. Behavioral assays quantified roaming and dwelling states using video recordings analyzed with WormLab, and CRISPR-engineered alleles tested the causal roles of candidate variants in the gap-2 gene.

Results: Natural variation in daf-7 ASJ expression was observed among wild strains, with N2 showing the lowest levels. Two gap-2 missense variants (S64T and S11L) were identified that increased daf-7 ASJ expression and promoted roaming behavior relative to wild type. These effects were partially dependent on daf-7 function and acted cell nonautonomously through ADE neurons. The variants were prevalent in global populations, especially in European and African isolates.

Conclusions: The findings demonstrate that natural gap-2 variants modulate neuroendocrine daf-7 expression to influence foraging behavior. This work links genetic variation in neuronal signaling pathways to behavioral diversity in C. elegans and illustrates how neuroendocrine regulation contributes to adaptive behavioral traits.