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To date, 36 FLPs encoded by seventeen flp genes flp-1 , 3 , 5 , 6 , 8 , 9 , 11 , 12 , 13 , 14 , 16 , 18 , 19 , 22 , 24 , 26 , and 33 have been isolated Rosoff et al. Husson and L. Schoofs, pers. Indeed, the identification of flp was based on the biochemical isolation of the peptide. Two FLPs that are not encoded by any of the identified flp genes have also been isolated Davis and Stretton, ; N. Marks and A. Stretton, pers. In the recent peptidomic analysis by Husson and coworkers , twenty nine NLPs encoded by 19 nlp genes were isolated see Table 3 , suggesting that many of the NLPs are also likely to be produced in C.

These data also indicate that is likely to be an underestimate of the total number of neuropeptide genes. Peptides identical to some of the predicted FLPs have been isolated from related nematodes see Table 4 , such as Ascaris suum Cowden et al. To date, most of the isolated peptides in related nematodes belong to the FLP family Yew et al. Similarly, several of the predicted NLPs are similar to peptides isolated from other invertebrates Nathoo et al.

These data suggest that many of the predicted neuropeptides are indeed produced and highlight the rich diversity of neuropeptides in C. Based on the expression pattern of the peptides, the peptides are likely to participate in a multitude of behaviors, including dauer formation, locomotion, egg-laying, and mechano- and chemosensation. To determine the function of the different neuropeptides, the most common strategy has been to inactivate or overexpress specific neuropeptide genes.

This strategy has certain drawbacks with large neuropeptide superfamilies because of the possible functional overlap among the family members. Several neuropeptides, for instance, may bind and activate the same receptor. Using RNAi to decrease neuropeptide activity has not been routinely performed because of the inefficiency of RNAi in neurons Simmer et al. Nevertheless, recent experiments have shown that several of the neuropeptide genes have unique functions.

Newly hatched first larval stage L1 animals sample their environment to assess its qualities for reproductive growth. In the absence of food, newly hatched L1 animals will arrest reproductive growth and remain in this arrested state until a food source becomes available Johnson et al. The decision to enter reproductive growth after hatching is dependent on the activity of DAF-2 , an insulin-like receptor, and ASNA-1 , an ATPase that acts non-cell autonomously and regulates the insulin pathway see below; Gems et al.

Under continued exposure to harsh environmental conditions, such as overcrowding, high temperatures, or a scarce food supply during L1 or L2, C. After L2, animals enter the dauer state rather than L3 and remain in the dauer state until conditions improve, whereupon they exit the dauer state and resume the lifecycle as L4 animals Cassada and Russell, Loss of either pathway results in constitutive dauer formation, indicating that the pathways function independently.

DAF-2 also functions to determine lifespan Kenyon et al. DAF-2 is the closest homologue to the mammalian insulin-like receptor superfamily Kimura et al. Members of the insulin superfamily are encoded by the ins genes and daf in C. Only two insulin-family genes that have been inactivated by mutation have been examined thus far.

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INS-1 is most similar to mammalian insulin Pierce et al. Loss of ins-1 has no effect on dauer formation or longevity Pierce et al. By contrast, the daf sa mutation causes transient dauer formation Malone and Thomas, The mutation is likely to act as a dominant negative whereby the daf sa gene product antagonizes DAF-2 activity Li et al. Consistent with this hypothesis, levels of a P daf ::GFP transgene are decreased during starvation or application of dauer pheromone Li et al. Expression of the P daf ::GFP transgene is found in an increasing number of cells as the animal ages Li et al.

If other insulin-like peptides also signal through the DAF-2 receptor, then perturbations of other ins genes may enhance or suppress the phenotypes of daf-2 and daf mutants. The phenotypes caused by overexpression of several ins genes, using their endogenous promoters, were examined in different daf backgrounds. However, overexpression of ins-9 or of ins and ins in combination in a wild-type or daf-2 mutant background caused embryonic or larval arrest, a phenotype similar to one shown by some daf-2 alleles Pierce et al. Overexpression of ins-4 or ins-6 can suppress or partially suppress, respectively, the daf sa mutation, suggesting that INS-4 or INS-6 can functionally substitute for DAF and activate the DAF-2 receptor when present at high levels Li et al.

By contrast, overexpression of ins-7 , 9 , 17 , 21 , 22 , and 23 did not suppress the daf sa mutation Li et al. These data indicate that several insulin-like ligands signal through or affect DAF-2 activity to affect developmental growth and dauer formation, while other insulin-like ligands signal through other non-DAF-2 insulin receptors. What are the roles of the other ins genes? Until mutants are isolated, the function of this large class of neuropeptides is largely unknown. Recently, INS-1 was identified as a key neuropeptide in the integration of behavior with the functional state of the animal.

When placed on a thermal gradient well-fed animals move towards the temperature on which they were cultivated, whereas starved animals avoid the temperature at which they were cultivated Hedgecock and Russell, Well-fed ins-1 mutants exhibit normal thermotaxis, indicating that the basic thermosensory properties of AFD are intact in the mutants. Similar to starved wild-type animals, starved ins-1 animals slow when encountering food, demonstrating that ins-1 animals can recognize their starvation state Kodama et al.

However, starved ins-1 mutants move towards rather than away from their cultivation temperature, presumably because they cannot integrate cultivation temperature with starvation state Kodama et al. This integration defect can be rescued by expression of ins-1 in different neurons and is partially suppressed by mutations in daf-2 and age-1 , suggesting that INS-1 acts non-cell autonomously to antagonize signaling through the DAF-2 receptor Kodama et al. Wild-type animals normally chemotax towards sodium chloride NaCl Ward, However, after pre-exposure to NaCl, starved, but not well-fed animals will avoid NaCl; this behavior is referred to as salt chemotaxis learning Saeki et al.

Several mutants, including daf-2 , age-1 , pdk-1 , akt-1 , and ins-1 , are defective for salt chemotaxis learning Tomioka et al. Hence, INS-1 is involved in multiple integration events and whether it activates or antagonizes DAF-2 signaling is context dependent. Acetylcholine is the primary excitatory transmitter at the neuromuscular junction in C. Aldicarb blocks the effects of acetylcholinesterase, thereby increasing the amount of acetylcholine at the synapse and causing paralysis and lethality Nguyen et al.

To identify genes that are resistant to aldicarb, a genome-wide RNAi screen was performed on eri-1 ;linB or eri-1 ; dgk-1 linB mutants, which have a sensitized background for RNAi Sieburth et al.


In addition to the processing enzymes, decreased activity of four neuropeptide genes, two ins genes ins and ins , one flp gene flp-1 , and one nlp gene nlp , conferred aldicarb-resistance, suggesting that the peptides encoded by these genes modulate acetylcholine signaling Sieburth et al. Deletion mutants have been isolated for eleven flp genes Nelson et al. Inactivation of flp-1 causes several defects, including hyperactive movement Nelson et al. Ashrafi, pers. FLP-1 peptides are also necessary for down-regulation of egg laying in the absence of food Waggoner et al.

The remaining flp mutants are currently being examined. Because so many flp genes have overlapping expression patterns, the function of these genes may also overlap and, therefore, be difficult to tease apart.

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Hence, deletion mutants are being screened on a large variety of behavioral assays. For instance, the swimming or thrashing assay, which involves placing animals in physiological buffer and counting the number of thrashes per minute, is more sensitive for detecting locomotion defects than examining the animal's movement on a solid surface.

By the thrashing assay, flp-9 was found to thrash significantly less actively than wild-type animals unpubl. Hence, to understand how the FLPs function, mutants will be examined for subtle defects, animals carrying multiple knockouts need to be isolated, and the receptor to which the peptides bind must be identified, as was done in the case of flp The function of flp will be discussed in conjunction with the function of its receptor, NPR Although no nlp mutant has been examined thus far, several of the nlp genes may function as anti-microbial peptides.

In microarray analyses to identify genes whose expression levels are changed in response to fungal or bacterial insults, expression of nlp , 31 , and 33 was induced Couillault et al. Furthermore, the peptide encoded by nlp has anti-microbial activity and protects against fungal infection Couillault et al.

The peptides encoded by nlp , 25 , 27 , 28 , and 30 are similar to those encoded by nlp , 31 , and 33 , suggesting that these peptides also have anti-microbial functions Couillault et al. By contrast, nlp and 27 are also expressed in neurons Nathoo et al. The expression patterns of nlp and 28 are unknown, so whether the peptides encoded by these genes also function as anti-microbial agents is unknown. As described above, nlp is involved in modulating acetylcholine signaling Sieburth et al.

As mentioned above, the function of a specific neuropeptide may be difficult to discern. Not only are multiple neuropeptides expressed in a single cell, but a specific neuropeptide may bind to multiple receptors. As illustrated above with the insulin-like peptides and their receptors, an alternative strategy to determine the function of neuropeptides is to inactivate the receptors to which the peptides bind. Of the G-protein-coupled receptors in C. Sixty G-protein receptors that were predicted to bind either a small molecule transmitter or a neuropeptide were inactivated by RNAi and screened for behavioral deficits Keating et al.

RNAi of six receptors, C16D6. The phenotypes from the RNAi data were confirmed in two cases by the isolation of deletion mutants in T05A1. Several of the ligands for these receptors have now been identified see below. To match FLP ligands to specific G protein-coupled receptor binding partners, several groups have expressed candidate receptors in either heterologous cells or Xenopus oocytes Kubiak et al.

Different FLP ligands were applied and several assays were used as the read out. Some of the receptors are activated by multiple peptides encoded by one gene, while other receptors can be activated by peptides encoded by different genes. A few examples will be described below. Binding of the cognate ligand to the receptor would presumably activate the receptor, thereby activating G proteins. Nevertheless, Mertens and co-workers found that C26F1. A FLP receptor can also bind to a diverse group of peptides with a range of activities.

Sleep, neuropeptides and proteases

The Y59H11AL. Note that peptides encoded by flp-7 bind to two receptors, C26F1. Where these two receptors are expressed may give us some clues as to how FLP-7 peptides affect behavior. Given that a FLP receptor can bind to multiple peptides encoded by different genes and a single peptide can bind to multiple receptors, the potential complexity of peptide actions in C.

Mutations in the NPR-1 receptor affect aggregation behavior de Bono and Bargmann, and tolerance to alcohol Davies et al. On an agar plate with a bacterial food source, wild-type animals feed alone referred to as solitary feeding ; a mutation in npr-1 causes the animals to aggregate during feeding referred to as social feeding and accumulate at the edges of the bacteria referred to as bordering behavior; de Bono and Bargmann, The aggregation behavior of npr-1 mutants can be suppressed by mutations in gcy or gcy Cheung et al.

GCY guanylate cyclase binds oxygen, and the aggregation behavior of npr-1 mutants may be related to oxygen levels in the local environment of the animals Gray et al. To identify the NPR-1 ligand, the de Bono group injected constructs for NPR-1 as well as inwardly rectifying potassium channels into Xenopus oocytes, and screened for receptor activation of the potassium channels Rogers et al. Because no neuropeptide Y is present in C. Both Rogers et al. Animals carrying a mutation in flp display only mild aggregation compared to npr-1 mutants Rogers et al. Two explanations may account for the difference in phenotypes between the FLP ligand and the NPR-1 receptor mutants.

The first is that the flp mutation may be a partial loss of function allele instead of a null allele; the second is that FLP ligands, which also bind NPR-1 , may functionally substitute for the loss of FLP ligands Rogers et al. Because many of the FLPs have been also found in parasitic nematodes Cowden et al.

Muscles of exposed pharyngeal terminal bulbs were impaled with microelectrodes to record changes of activity and action potential frequency. Surprisingly, many of the tested FLPs modulated the action potential frequency Rogers et al. Peptides encoded by flp-5 , 6 , 8 , and 14 increased the action potential frequency, while peptides encoded by flp-1 , 3 , 9 , 13 , and 16 decreased the action potential frequency. These data are consistent with the expression of some of these FLPs in the pharynx Kim and Li, and suggest that multiple FLPs are involved in feeding behavior.

Similarly, application of peptides encoded by 20 flp genes had a range of effects on body wall, reproductive, and pharyngeal muscle of Ascaris suum Fellowes et al. On Ascaris muscle, different FLPs can activate different ion channels. The response to FLPs can also be more complex. More recently, Stretton and coworkers have begun to characterize the effects of C. Overall, the number of FLPs that can elicit physiological effects is striking and highlights the complex and intricate ways that different FLPs can modulate synaptic and muscle activity.

The diversity of neuropeptides in C. Although many of the peptides appear to be invertebrate specific, the insulin-like and FMRFamide-related peptides have counterparts in mammals. The daunting task of determining the regulation and functions of the different peptides remains.

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This task is complicated by the overlapping expression and redundant functions of the different peptides, as well as by their ability to bind multiple receptors, and, likewise, by the ability of the receptors to bind multiple ligands. While most, if not all, FLPs and NLPs are likely to signal through G protein-coupled receptors and the insulin-like ligands to signal through receptor tyrosine kinases, the identities of these receptors are still largely unknown. Despite the limited information available thus far, we envision that neuropeptides are involved in all behaviors in C.

We thank K. Ashrafi, A. Hart, A. Maule, P. McVeigh, S. McIntire, L. Schoofs, and A. Stretton for sharing unpublished data, O. Hobert with revisions of expression patterns, C. Ferguson for comments on the manuscript, and A. Hart and A. Maule for helpful discussions. This work was supported by grants from the NIH to C.

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Bargmann, C. Neurobiology of the Caenorhabditis elegans genome. Science , — Abstract Article. Control of larval development by chemosensory neurons in Caenorhabditis elegans.

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Bonini, J. Identification and characterization of two G protein-coupled receptors for neuropeptide FF. Bowman, J. Peptides 17 , — Brownlee, D.

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  6. Nematode neuropeptides: Localization, isolation and functions. Today 12 , — The range and biological activity of FMRFamide-related peptides and classical neurotransmitters in nematodes. Actions of nematode FMRFamide-related peptides on the pharyngeal muscle of the parasitic nematode, Ascaris suum. Genome sequence of the nematode C. Cai, T. Cassada, R. The dauerlarva, a post-embryonic developmental variant of the nematode Caenorhabditis elegans.

    Cazzamali, G, and Grimmelikhuijzen, C. Molecular cloning and functional expression of the first insect FMRFamide receptor. Cheung, B. Soluble guanylate cyclases act in neurons exposed to the body fluid to promote C. Couillault, C. Cowden, C. Localization and differential expression of FMRFamide-like immunoreactivity in the nematode Ascaris suum.

    AF2, an Ascaris neuropeptide: isolation, sequence, and bioactivity. Peptides 14 , — Peptides 16 , — AF1, a sequenced bioactive neuropeptide isolated from the nematode Ascaris suum. Neuron 2 , — Davies, A. Natural variation in the npr-1 gene modifies ethanol responses of wild strains of C. Neuron 42 , — Davis, R. The motornervous system of Ascaris : eletrophysiology and anatomy of the neurons and their control by neuromodulators.

    Parasitology , S97—S Structure-activity relationships of 18 endogenous neuropeptides on the motor nervous system of the nematode Ascaris suum. Share Give access Share full text access. Share full text access. Please review our Terms and Conditions of Use and check box below to share full-text version of article. Figure 1 Open in figure viewer PowerPoint. Figure 2 Open in figure viewer PowerPoint. Figure 3 Open in figure viewer PowerPoint.

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    Compartmentation Nonetheless, Fig. Abbott C. Langner and S. Ansorge , eds , pp. Crossref Google Scholar. PubMed Google Scholar. Google Scholar. Citing Literature. Volume , Issue 5 December Pages Figures References Related Information. Close Figure Viewer. Browse All Figures Return to Figure. Previous Figure Next Figure. Email or Customer ID. Forgot password? Old Password. New Password. Password Changed Successfully Your password has been changed. Prepropeptides comprise of a signal peptide which directs the protein to the secretory pathway , progenitors of mature peptides the biologically-active peptides , spacer peptides peptide fragments with no known biological function and non-conserved sequences and cleavage sites monobasic and dibasic.

    Each precursor can give rise to one or more mature neuropeptides or peptide hormones. The number of mature peptides produced from a given precursor can vary from one insect species to another. These can either be 1 a set of very similar peptides with partly conserved sequences and thus similar receptor activation properties such as tachykinin-related peptides, AstBs and FMRFamides , or 2 in some cases peptides with distinct sequences and functions. There are also examples of peptides with similar sequences being produced by paralogs and splice variants. Insulin-like peptides are encoded by up to 38 paralogous genes in the moth Bombyx mori and 8 genes in Drosophila see Mizoguchi and Okamoto, The orcokinin gene in insects produces two different neuropeptide precursors by alternative splicing: orcokinin A and orcokinin B Jiang et al, A typical prepropeptide and its biosynthesis and processing is shown in the diagram.

    All information on the neuropeptides More Info provided by Dr. Meet Zandawala and Prof. Dick R. Below is a list of insect neuropeptide families. Where applicable, their synonyms are also listed. More Info.