Non-Transgenic Functional Rescue of Neuropeptides

Animals constantly respond to changes in their environment and internal states via neuromodulation. Neuropeptide genes modulate neural circuits by encoding either multiple copies of the same neuropeptide or different neuropeptides. This architectural complexity makes it difficult to determine the function of discrete and active neuropeptides. Here, we present a novel genetic tool that facilitates functional analysis of individual peptides. We engineered Escherichia coli bacteria to express active peptides and fed loss-of-function Caenorhabditis elegans to rescue gene activity. Using this approach, we rescued the activity of different neuropeptide genes with varying lengths and functions: trh-1, ins-6, and pdf-1. While some peptides are functionally redundant, others exhibited unique and previously uncharacterized functions. The mechanism of peptide uptake is reminiscent of RNA interference, suggesting convergent mechanisms of gene regulation in organisms. Our rescue-by-feeding paradigm provides a high-throughput screening strategy to elucidate the functional landscape of neuropeptide genes regulating different behavioral and physiological processes.