FMRFamide (Phe-Met-Arg-Phe-NH2) and related peptides (FaRPs) have been found throughout the animal kingdom, where they are involved in many behaviors. We previously identified 22 genes comprising the flp gene family that encodes FaRPs in Caenorhabditis elegans; in this paper we report the identification of another flp gene, flp-23. As a first step toward determining their functional roles in C. elegans, we examined the cell-specific expression pattern of the flp gene family. Of the 19 flp genes examined, each gene is expressed in a distinct set of cells; these cells include interneurons, motor neurons, and sensory neurons that are involved in multiple behaviors, as well as supporting cells, muscle cells, and epidermal cells. Several flp genes show sex-specific expression patterns. Furthermore, we find that expression of two flp genes changes in response to the developmental state of the animal. Many neurons express multiple flp genes. To investigate how flp genes are regulated in different neuronal subtypes, we examined flp expression in a small, well-defined subset of neurons, the mechanosensory neurons. Mutations in the unc-86 and mec-3 genes, which are necessary for the production and differentiation of the mechanosensory neurons, result in the complete loss of flp-4, flp-8, and flp-20 expression in mechanosensory neurons. Collectively, these data indicate that members of the flp gene family are likely to influence multiple behaviors and that their regulation can be dependent on the developmental state of the organism.

Social and solitary feeding in natural Caenorhabditis elegans isolates are associated with two alleles of the orphan G-protein-coupled receptor (GPCR) NPR-1: social feeders contain NPR-1 215F, whereas solitary feeders contain NPR-1 215V. Here we identify FMRFamide-related neuropeptides (FaRPs) encoded by the flp-18 and flp-21 genes as NPR-1 ligands and show that these peptides can differentially activate the NPR-1 215F and NPR-1 215V receptors. Multicopy overexpression of flp-21 transformed wild social animals into solitary feeders. Conversely, a flp-21 deletion partially phenocopied the npr-1(null) phenotype, which is consistent with NPR-1 activation by FLP-21 in vivo but also implicates other ligands for NPR-1. Phylogenetic studies indicate that the dominant npr-1 215V allele likely arose from an ancestral npr-1 215F gene in C. elegans. Our data suggest a model in which solitary feeding evolved in an ancestral social strain of C. elegans by a gain-of-function mutation that modified the response of NPR-1 to FLP-18 and FLP-21 ligands.

The role of neuropeptides in modulating behavior is slowly being elucidated. With the sequencing of the C. elegans genome, the extent of the neuropeptide genes in C. elegans can be determined. To date, 113 neuropeptide genes encoding over 250 distinct neuropeptides have been identified. Of these, 40 genes encode insulin-like peptides, 31 genes encode FMRFamide-related peptides, and 42 genes encode non-insulin, non-FMRFamide-related neuropeptides. As in other systems, C. elegans neuropeptides are derived from precursor molecules that must be post-translationally processed to yield the active peptides. These precursor molecules contain a single peptide, multiple copies of a single peptide, multiple distinct peptides, or any combination thereof. The neuropeptide genes are expressed extensively throughout the nervous system, including in sensory, motor, and interneurons. In addition, some of the genes are also expressed in non-neuronal tissues, such as the somatic gonad, intestine, and vulval hypodermis. To address the effects of neuropeptides on C. elegans behavior, animals in which the different neuropeptide genes are inactivated or overexpressed are being isolated. In a complementary approach the receptors to which the neuropeptides bind are also being identified and examined. Among the knockout animals analyzed thus far, defects in locomotion, dauer formation, egg laying, ethanol response, and social behavior have been reported. These data suggest that neuropeptides have a modulatory role in many, if not all, behaviors in C. elegans.

Dominant mutations in the amyloid precursor protein (APP) gene are associated with rare cases of familial Alzheimer's disease; however, the normal functions of APP and related proteins remain unclear. The nematode Caenorhabditis elegans has a single APP-related gene, apl-1, that is expressed in multiple tissues. Loss of apl-1 disrupts several developmental processes, including molting and morphogenesis, and results in larval lethality. The apl-1 lethality can be rescued by neuronal expression of the extracellular domain of APL-1. These data highlight the importance of the extracellular domain of an APP family member and suggest that APL-1 acts noncell-autonomously during development. Overexpression of APL-1 also causes several defects, including a high level of larval lethality. Decreased activity of sel-12, a C. elegans homologue of the human ␥-secretase component presenilin 1, partially rescues the lethality associated with APL-1 overexpression, suggesting that SEL-12 activity regulates APL-1 activity either directly or indirectly. Determining the in vivo functions of APP in mammals is complicated by the presence of two APP-related genes, APLP1 and APLP2 (for review see ref. 5). APP and APP-related proteins share two conserved domains in the extracellular region (E1 and E2) and one in the cytoplasmic domain, but the APP-related proteins do not contain the ␤-amyloid peptide (5). Mice in which APP, APLP1, or APLP2 is inactivated are viable and have minor behavioral and growth deficits (6-8). However, inactivation of APLP2 and either APP or APLP1 results in early postnatal lethality (6,8), indicating that the APP family is essential for viability. The brains of double knockout animals exhibit no obvious morphological defects (6, 8). By contrast, animals in which the entire APP gene family is inactivated show cortical dysplasia and type 2 lissencephaly, indicating that the APP gene family is necessary for neurodevelopment and adhesion (9).Although no APP gene has been identified in Drosophila melanogaster or Caenorhabditis elegans, each organism contains a single APP-related gene (10, 11). Inactivation of the Drosophila APP-related gene, Appl, causes abnormal synaptic differentiation (12), axonal transport (13,14), and phototactic behavior (15), the latter of which can be partially rescued with a human APP transgene (15). Expression of human APP in Drosophila wing imaginal discs results in a blistered wing phenotype, showing that overexpression of APP can disrupt cell adhesion in the transgenic animals (16).In this article, we examine the role of apl-1 in C. elegans. Zambrano et al. (17) have reported mild pharyngeal defects when apl-1 activity is decreased by dsRNA-mediated interference by feeding. We genetically inactivated apl-1 and found that, like the mammalian APP gene family, apl-1 has an essential role in C. elegans. In particular, APL-1 is necessary for proper molting and morphogenesis. Furthermore, expression of the extracellular domain of APL-1 in neurons is sufficient to rescue the apl-1 lethality. Th...

Neuropeptides serve as important signaling molecules in the nervous system. The FMRFamide (Phe-Met-Arg-Phe-amide)-related neuropeptide gene family in the nematode Caenorhabditis elegans is composed of at least 18 genes that may encode 53 distinct FMRFamide-related peptides. Disruption of one of these genes, flp-1, causes numerous behavioral defects, including uncoordination, hyperactivity, and insensitivity to high osmolarity. Conversely, overexpression of flp-1 results in the reciprocal phenotypes. On the basis of epistasis analysis, flp-1 gene products appear to signal upstream of a G protein-coupled second messenger system. These results demonstrate that varying the levels of FLP-1 neuropeptides can profoundly affect behavior and that members of this large neuropeptide gene family are not functionally redundant in C. elegans.

Advances in research and technology has increased our quality of life, allowed us to combat diseases, and achieve increased longevity. Unfortunately, increased longevity is accompanied by a rise in the incidences of age-related diseases such as Alzheimer’s disease (AD). AD is the sixth leading cause of death, and one of the leading causes of dementia amongst the aged population in the USA. It is a progressive neurodegenerative disorder, characterized by the prevalence of extracellular Aβ plaques and intracellular neurofibrillary tangles, derived from the proteolysis of the amyloid precursor protein (APP) and the hyperphosphorylation of microtubule-associated protein tau, respectively. Despite years of extensive research, the molecular mechanisms that underlie the pathology of AD remain unclear. Model organisms, such as the nematode, Caenorhabditis elegans, present a complementary approach to addressing these questions. C. elegans has many advantages as a model system to study AD and other neurodegenerative diseases. Like their mammalian counterparts, they have complex biochemical pathways, most of which are conserved. Genes in which mutations are correlated with AD have counterparts in C. elegans, including an APP-related gene, apl-1, a tau homolog, ptl-1, and presenilin homologs, such as sel-12 and hop-1. Since the neuronal connectivity in C. elegans has already been established, C. elegans is also advantageous in modeling learning and memory impairments seen during AD. This article addresses the insights C. elegans provide in studying AD and other neurodegenerative diseases. Additionally, we explore the advantages and drawbacks associated with using this model.

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Spinal Muscular Atrophy (SMA) is caused by diminished function of the Survival of Motor Neuron (SMN) protein, but the molecular pathways critical for SMA pathology remain elusive. We have used genetic approaches in invertebrate models to identify conserved SMN loss of function modifier genes. Drosophila melanogaster and Caenorhabditis elegans each have a single gene encoding a protein orthologous to human SMN; diminished function of these invertebrate genes causes lethality and neuromuscular defects. To find genes that modulate SMN function defects across species, two approaches were used. First, a genome-wide RNAi screen for C. elegans SMN modifier genes was undertaken, yielding four genes. Second, we tested the conservation of modifier gene function across species; genes identified in one invertebrate model were tested for function in the other invertebrate model. Drosophila orthologs of two genes, which were identified originally in C. elegans, modified Drosophila SMN loss of function defects. C. elegans orthologs of twelve genes, which were originally identified in a previous Drosophila screen, modified C. elegans SMN loss of function defects. Bioinformatic analysis of the conserved, cross-species, modifier genes suggests that conserved cellular pathways, specifically endocytosis and mRNA regulation, act as critical genetic modifiers of SMN loss of function defects across species.