The FMRFamide-Like Peptide Family in Nematodes

Abstract

In the three decades since the FMRFamide peptide was isolated from the mollusk Macrocallista nimbosa, structurally similar peptides sharing a C-terminal RFamide motif have been identified across the animal kingdom. FMRFamide-like peptides (FLPs) represent the largest known family of neuropeptides in invertebrates. In the phylum Nematoda, at least 32 flp-genes are classified, making the FLP system of nematodes unusually complex. The diversity of the nematode FLP complement is most extensively mapped in Caenorhabditis elegans, where over 70 FLPs have been predicted. FLPs have shown to be expressed in the majority of the 302 C. elegans neurons including interneurons, sensory neurons, and motor neurons. The vast expression of FLPs is reflected in the broad functional repertoire of nematode FLP signaling, including neuroendocrine and neuromodulatory effects on locomotory activity, reproduction, feeding, and behavior. In contrast to the many identified nematode FLPs, only few peptides have been assigned a receptor and there is the need to clarify the pathway components and working mechanisms of the FLP signaling network. Here, we review the diversity, distribution, and functions of FLPs in nematodes.

Keywords: C. elegans; FMRFamide-like peptides; G protein-coupled receptor; feeding behavior; nematodes; neuropeptide; reproduction.

Figure 1

FLP signaling regulates C. elegans foraging and metabolism. (A) FLP-18 peptides are released from AIY in response to sensory cues relaying food availability. By acting on the receptors NPR-4 in the intestine and NPR-5 in ciliated neurons, FLP-18 peptides control fat storage; while activation of NPR-5 in ASJ neurons regulates dauer formation. (B) To regulate odor responses and foraging strategy, FLP-18 peptides signal through NPR-4 in AVA and RIV neurons that control reversal frequency and turning bias, respectively. (C) Peptidergic feedback modulates sensory responses in C. elegans. In response to odor, the AWC olfactory neuron releases NLP-1 neuropeptides, which act on the NPR-11 receptor on AIA to modulate INS-1 peptide secretion. INS-1 subsequently closes the feedback loop by modulating AWC’s responsiveness to sensory stimuli. AIA could act as a local integrator of sensory information, with FLP sensory peptides driving similar neuropeptidergic feedback loops to modulate the responsiveness to sensory stimuli [adapted from Ref. (, –121)].

Figure 2

Inhibition of the RMG interneuron by NPR-1. Signaling from ASH and ADL neurons induces aggregation through gap junctions with RMG. RMG is the hub neuron of a gap junction network connecting various sensory neurons known to trigger aggregation. ASH and ADL also mediate acute avoidance behavior through synaptic signaling. Both types of connections are differentially regulated by the NPR-1 receptor, with FLP signaling inhibiting the gap junction driven activation of RMG and not being essential to ASH-mediated avoidance [adapted from Ref. (100,151)].

Figure 3

FLP signaling suppresses egg-laying in unsuitable environments. BAG neurons release FLP-17 neuropeptides in response to unfavorable conditions. These peptides are able to activate the EGL-6 receptor on HSN motor neurons, hereby inhibiting egg-laying. Release of FLP-10 by the vulva and spermatheca along with subsequent EGL-6 signaling further inhibits egg-laying, with the exact triggering stimuli still uncharacterized. Under unfavorable conditions, cholinergic signals (ACh) may be independently invoked by other sensory circuits to synergistically inhibit egg-laying [adapted from Ref. (53,81)].