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[
1980]
The nematodes form a very important group of animals that have received much less study than deserved. They appear to be nearly as important in human health and agriculture as insects, and yet there are ten times as many entries in Biological Abstracts for the latter. Even from a less ethnocentric point of view, nematodes are significant. Hyman (1951) estimates 500,000 nematode species, which is of the same order as is the number of insect species. In soil, where comparisons have been made, the biomass of the two groups is roughly equal. The great disparity in research effort is simply because nematodes are much less visible to the casual observer. As a consequence of this situation, there is a need for basic biological research on nematodes. Much of the required work could be done on any typical nematode species, and since the free-living microphagous forms are most convenient to work with, they are of great interest. One of the areas in which basic knowledge is lacking for this group is that of behavior. This void is particularly surprising in view of the fact that behavior is presumably one of the more important aspects of parasitic lifestyles. It is also unfortunate from the point of view of basic behavioral biology. Nematodes and their close relatives occupy a unique place in the evolution of the nervous system. They are the only readily studied organisms that have been shown to have a centralized nervous system made up of a specific and countable number of neurons. The nematodes that have been examined have about 200 neurons depending on the species. In contrast, two annelids that have been studied have 10*4 and 10*5 neurons, and an arthropod is estimated to have 10*5 neurons. On the other hand, more primitive nervous systems are apparently not eutelic and often consist of a dispersed nerve net. Thus, it is of general biological interest to determine the behavioral capacities of
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Molecular Neurobiology,
2004]
Invertebrate model systems have a long history of generating new insights into neuronal signaling systems. This review focuses on cyclic GMP signaling and describes recent advances in understanding the properties and functions of guanylyl cyclases in invertebrates. The sequencing of three invertebrate genomes has provided a complete catalog of the guanylyl cyclases in C. elegans, Drosophila, and the mosquito Anopheles gambiae. Using this data and that from cloned guanylyl cyclases in Manduca sexta, C. elegans, and Drosophila, plus predictions and models from vertebrate guanylyl cyclases, evidence is presented that there is a much broader array of properties for these enzymes than previously realized. In addition to the classic homodimeric receptor guanylyl cyclases, C. elegans has at least two receptor guanylyl cyclases that are predicted to require heterodimer formation for activity. Soluble guanylyl cyclases are generally recognized as being obligate heterodimers that are activated by nitric oxide (NO). Some of the soluble guanylyl cyclases in C. elegans may heterodimeric, but all appear to be insensitive to NO. The beta2 soluble guanylyl cyclase subunit in mammals and similar ones in Manduca and Drosophila are active in the absence of additional subunits and there is evidence that Drosophila and Anopheles also express an additional subunit that enhances this activity.
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Trends Endocrinol Metab,
2008]
Nuclear receptors are a class of hormone-gated transcription factors found in metazoans that regulate global changes in gene expression when bound to their cognate ligands. Despite species diversification, nuclear receptors function similarly across taxa, having fundamental roles in detecting intrinsic and environmental signals, and subsequently in coordinating transcriptional cascades that direct reproduction, development, metabolism and homeostasis. These endocrine receptors function in vivo in part as molecular switches and timers that regulate transcriptional cascades. Several Caenorhabditis elegans nuclear receptors integrate intrinsic and extrinsic signals to regulate the dauer diapause and longevity, molting, and heterochronic circuits of development, and are comparable to similar in vivo endocrine regulated processes in other animals.
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Novartis Found Symp,
2002]
Genetics, genomics and electrophysiology are transforming our understanding of the nicotinic acetylcholine receptors (nAChRs). Caenorhabditis elegans contains the largest known family of nAChR subunit genes (27 members), while Drosophila melanogaster contains an exclusively neuronal nAChR gene family (10 members). In C. elegans, several genetic screens have enabled the identification of nAChR subunits, along with novel proteins that act upstream and downstream of functional nAChRs. The C. elegans genome project has identified many new candidate nAChR subunits and the calculated electrostatic potential energy profiles for the M2 channel-lining regions predict considerable functional diversity. The respective roles of subunits are under investigation using forward and reverse genetics. Electrophysiological and reporter genes studies have demonstrated roles for particular subunits in levamisole-sensitive muscle nAChRs and a role for nAChRs in pharyngeal pumping. Recombinant homomeric and heteromeric C. elegans nAChRs have been expressed in Xenopus laevis oocytes. In D. melanogaster, three new nAChR alpha subunits have been cloned, one of which shows multiple variant transcripts arising from alternative splicing and A-to-I pre-mRNA editing. Thus, studies on the genetic model organisms C. elegans and D. melanogaster have revealed different routes to generating molecular and functional diversity in the nAChR gene family and are providing new insights into the in vivo functions of individual family members.
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Neurotoxicology,
2008]
Manganese (Mn) is a transition metal that is essential for normal cell growth and development, but is toxic at high concentrations. While Mn deficiency is uncommon in humans, Mn toxicity is known to be readily prevalent due to occupational overexposure in miners, smelters and possibly welders. Excessive exposure to Mn can cause Parkinson''s disease-like syndrome; patients typically exhibit extrapyramidal symptoms that include tremor, rigidity and hypokinesia [Calne DB, Chu NS, Huang CC, Lu CS, Olanow W. Manganism and idiopathic parkinsonism: similarities and differences. Neurology 1994;44(9):1583-6; Dobson AW, Erikson KM, Aschner M. Manganese neurotoxicity. Ann NY Acad Sci 2004;1012:115-28]. Mn-induced motor neuron diseases have been the subjects of numerous studies; however, this review is not intended to discuss its neurotoxic potential or its role in the etiology of motor neuron disorders. Rather, it will focus on Mn uptake and transport via the orthologues of the divalent metal transporter (DMT1) and its possible implications to Mn toxicity in various categories of eukaryotic systems, such as in vitro cell lines, in vivo rodents, the fruitfly, Drosophila melanogaster, the honeybee, Apis mellifera L., the nematode, Caenorhabditis elegans and the baker''s yeast, Saccharomyces cerevisiae.
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Mech Dev,
1999]
The study of sex determination in model organisms has been especially fruitful in increasing our understanding of developmental biology, gene regulation and evolutionary mechanisms. The free living nematode, Caenorhabditis elegans, can develop as one of two sexes; male or self-fertilizing hermaphrodite. Here we discuss the progress toward a genetic and molecular understanding of that decision. Numerous genetic loci have been identified that affect sexual fate, and epistasis analysis of these genes has led to a model of a regulatory hierarchy with stepwise negative interactions. It is becoming evident that many of the genes have numerous levels of regulation. We also discuss the apparent rapid rate of evolution that many of the sex determination proteins have undergone. Protein sequences of homologues from closely related species are more divergent than homologues of proteins involved in other developmental processes. Rapid evolution of sex determination genes may be a common theme throughout the animal kingdom.
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Invert Neurosci,
2008]
Automated analysis of C. elegans behaviour is a rapidly developing field, offering the possibility of behaviour-based, high-throughput drug screens and systematic phenotyping. Standard methods for parameterizing worm shapes and movements are emerging, and progress has been made towards overcoming the difficulties introduced by interactions between worms, as well as worm coiling and omega turning. Current methods have facilitated the identification of subtle phenotypes and the characterisation of roles of neurones in forward locomotion and chemotaxis, as well as the quantitative characterisation of behaviour choice and circadian patterns of activity. Given the speed with which C. elegans has been deployed in genetic screens and chemical screens, it is to be hoped that wormtrackers may eventually provide similar rapidity in assaying behavioural phenotypes. However, considerable progress must be made before this can be accomplished. In the case of genome-wide RNAi screens, for example, the presence in the worm genome of some 19,000 genes means that even the minimal user intervention in an automatic phenotyping system will be very costly. Nonetheless, recent advances have shown that drug actions on large numbers of worms can be tracked, raising hopes that high-throughput behavioural screens may soon be available.
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Hum Mol Genet,
2000]
A growing number of medical research teams have begun to explore the experimental advantages of using a genetic animal model, the nematode worm Caenorhabditis elegans, with a view to enhancing our understanding of genes underlying human congenital disorders. In this study, we have compared sequences of positionally cloned human disease genes with the C.elegans database of predicted genes. Drawing on examples from spinal muscular atrophy, polycystic kidney disease, muscular dystrophy and Alzheimer's disease, we illustrate how data from C.elegans can yield new insights into the function and interactions of human disease genes.
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Bioessays,
2004]
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that bring about a diversity of fast synaptic actions. Analysis of the Caenorhabditis elegans genome has revealed one of the most-extensive and diverse nAChR gene families known, consisting of at least 27 subunits. Striking variation with possible functional implications has been observed in normally conserved motifs at the acetylcholine-binding site and in the channel-lining region. Some nAChR subunits are particular to neurons whilst others are present in both neurons and muscles. The localization of subunits in non-synaptic regions suggests novel roles for nAChRs. Genetic and heterologous expression studies have identified a subset of nAChR subunits that are important drug targets while the study of mutants has identified genes functionally-linked to nAChRs. Future studies using C. elegans offer the prospect of increasing our understanding of the functional diversity of a complex nAChR gene family as well as addressing the role of nAChRs and associated proteins in human disorders.
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Translational Neuroscience,
2010]
The nematode Caenorhabditis elegans is a genetic model organism and the only animal with a complete nervous system wiring diagram. With only 302 neurons and 95 striated muscle cells, a rich array of mutants with defective locomotion and the facility for individual targeted gene knockdown by RNA interference, it lends itself to the exploration of gene function at nerve muscle junctions. With approximately 60% of human disease genes having a C. elegans homologue, there is growing interest in the deployment of lowcost, high-throughput, drug screens of nematode transgenic and mutant strains mimicking aspects of the pathology of devastating human neuromuscular disorders. Here we explore the contributions already made by C. elegans to our understanding of muscular dystrophies (Duchenne and Becker), spinal muscular atrophy, amyotrophic lateral sclerosis, Friedreichs ataxia, inclusion body myositis and the prospects for contributions to other neuromuscular disorders. A bottleneck to low-cost, in vivo, large-scale chemical library screening for new candidate therapies has been rapid, automated, behavioural phenotyping. Recent progress in quantifying simple swimming (thrashing) movements is making such screening possible and is expediting the translation of drug candidates towards the clinic.