The role of neuropeptides in modulating complex behavior in the mammalian nervous system is slowly being elucidated. The recent identification of neuropeptides involved in circadian rhythms, sleep patterns, and obesity highlights the diversity of behaviors in which neuropeptides play a role. Because neuropeptides are often multifunctional and have overlapping functions with other peptides, their precise role in many behaviors have been difficult to assess. We are interested in examining the function, regulation, and signaling pathways of a neuropeptide gene family in a simple model system, the roundworm Caenorhabditis elegans. The simplicity of the C. elegans nervous system and the ability to manipulate the animal genetically allows use of approaches in C. elegans not readily available in other systems, such as mammals. Furthermore, because the genome of C. elegans has been completely determined, we are able for the first time to target specific neuropeptide gene families for study. By BLAST searches, there are at least 54 predicted neuropeptide genes encoding over 100 distinct neuropeptides in C. elegans. We have focused on examining the FMRFamide-related gene family, which represents the single largest neuropeptide gene family in any organism. About 50 percent of the nerve cells in C. elegans use FMRFamide-related peptides (FaRPs). Over 23 C. elegans genes encode FaRPs, and at least one of these genes does not have functional overlap with the other genes. We will study the function of this gene family by isolating deletion mutants for each gene. In addition, we will begin to match the FaRP ligand to specific receptors by using a combined bioinformatics and experimental approach. Animals in which the receptors are inactivated will be isolated and characterized. Insights into how neuropeptides function in C. elegans may give clues into how neuropeptides are used in higher animals, such as man. In addition, because C. elegans is the current genetic model system for parasitic nematodes, elucidating the functions of neuropeptides and their signaling pathways may identify new antihelmintic drug targets.
