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[
WormBook,
2005]
Receptors of the LIN-12 /Notch family mediate cell-cell interactions during animal development, and aberrations in LIN-12 /Notch signaling have been implicated in human disease. Studies in C. elegans have been instrumental in defining the basic features of the LIN-12 /Notch pathway, the role of LIN-12 /Notch proteins as receptors for intercellular signals, the mechanism of signal transduction, and the regulation of LIN-12 /Notch signaling during cell fate decisions. This chapter is focused on detailing how the "awesome power of C. elegans genetics" has identified many core components and modulators of LIN-12 /Notch activity.
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[
WormBook,
2007]
Four biogenic amines: octopamine, tyramine, dopamine and serotonin act in C. elegans to modulate behavior in response to changing environmental cues. These neurotransmitters act at both neurons and muscles to affect egg laying, pharyngeal pumping, locomotion and learning. A variety of experimental approaches including genetic, imaging, biochemical and pharmacological analyses have been used to identify the enzymes and cells that make and release the amines and the cells and receptors that bind them. Dopamine and serotonin act through receptors and downstream signaling mechanisms similar to those that operate in the mammalian brain suggesting that C. elegans will provide a valuable model for understanding biogenic amine signaling in the brain.
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[
WormBook,
2006]
Nuclear receptors (NRs) are transcription factors typically regulated by lipophilic hormones, which coordinate metazoan metabolism, development and homeostasis. C. elegans has undergone a remarkable expansion of the family, harboring 284 of these receptors in its genome. Approximately 20 of them have been analyzed genetically, most of which correspond to conserved homologs in other metazoans. These NRs variously affect broad life history traits such as sex determination, molting, developmental timing, diapause, and life span. They also impact neural development, axon outgrowth and neuronal identity. Finally, they influence lipid and xenobiotic metabolism. The study of C. elegans NRs holds great promise for dissecting nuclear receptor signaling pathways in vivo in the context of complex endocrine networks.
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[
WormBook,
2005]
The most abundant synapses in the central nervous system of vertebrates are inhibitory synapses that use the neurotransmitter gamma-aminobutyric acid (GABA). GABA is also an important neurotransmitter in C. elegans; however, in contrast to vertebrates where GABA acts at synapses of the central nervous system, in nematodes GABA acts primarily at neuromuscular synapses. Specifically, GABA acts to relax the body muscles during locomotion and foraging and to contract the enteric muscles during defecation. The importance of this neurotransmitter for basic motor functions of the worm has facilitated the genetic analysis of proteins required for GABA function. Genetic screens have identified the GABA biosynthetic enzyme, the vesicular transporter, inhibitory and excitatory receptors, and a transcription factor required for the differentiation of GABA cell identity. The plasma membrane transporter and other GABA receptors have been identified by molecular criteria.
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[
WormBook,
2007]
Acetylcholine is the major excitatory neurotransmitter at nematode neuromuscular junctions, and more than a third of the cells in the C. elegans nervous system release acetylcholine. Through a combination of forward genetics, drug-resistance selections, and genomic analysis, mutants have been identified for all of the steps specifically required for cholinergic function. These include two enzymes, two transporters, and a bewildering assortment of receptors. Cholinergic transmission is involved, directly or indirectly, in many C. elegans behaviors, including locomotion, egg laying, feeding, and male mating.
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[
WormBook,
2006]
Most rapid excitatory synaptic signaling is mediated by glutamatergic neurotransmission. An important challenge in neurobiology is to understand the molecular architecture of functional glutamatergic synapses. By combining the techniques of genetics, molecular biology and electrophysiology in C. elegans we have the potential to identify and characterize the molecules that contribute to the function of glutamatergic synapses. In C. elegans both excitatory and inhibitory ionotropic glutamate receptors are linked to neural circuits and behavior. Genetic analysis has identified genes required for receptor expression, trafficking, localization, stabilization and function at synapses. Significantly, novel proteins required for glutamate receptor function have been discovered in the worm. These advances may also lead to a better understanding of glutamatergic signaling in vertebrates.
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[
WormBook,
2005]
TGF-beta superfamily ligands play fundamental roles in the development and physiology of diverse animal species. Genetic and genomic analyses in the model organism Caenorhabditis elegans have contributed to the understanding of TGF-beta -related signal transduction mechanisms. In this chapter, I describe the currently characterized TGF-beta -related signals and signal transduction cassettes in C. elegans. Homology searches of the genome identify five TGF-beta -related genes, for which functions have been identified for three. Two of the TGF-beta -related genes,
daf-7 and
dbl-1 , function through conventional signaling pathways. These signaling pathways are comprised of ser/thr kinase receptors, Smads, and transcription co-factors. A third TGF-beta -related gene,
unc-129 , functions in axonal guidance using novel signaling mechanisms. Thus, TGF-beta -related signaling in C. elegans proceeds via both conserved and novel paradigms that can inform studies in other animal systems.
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[
WormBook,
2010]
Ethanol is a widely used drug whose mechanism of action, despite intensive study, remains uncertain. Biochemical and electrophysiological experiments have identified receptors and ion channels whose functions are altered at physiological concentrations of ethanol. Yet, the contribution of these potential targets to its intoxicating or behavioral effects is unclear. Unbiased forward genetic screens for resistant or hypersensitive mutants represent an attractive means of identifying the relevant molecular targets or biochemical pathways mediating the behavioral effects of neuroactive compounds. C. elegans has proven to be a particularly useful system for such studies. The behavioral effects of ethanol occur at equivalent tissue concentrations in mammals and in C. elegans, suggesting the existence of conserved drug targets in the nervous system. This chapter reviews the results of studies directed toward determining the mechanisms of action of ethanol. Studies of the neural adaptations that occur with prolonged drug exposure are also discussed. The methods used to characterize the actions of ethanol should be applicable to the characterizations of other compounds that affect the behavior of C. elegans.
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[
WormBook,
2005]
Basement membranes are thin, specialized extracellular matrices surrounding most tissues in all metazoans. The compositions and functions of basement membranes have generally been well conserved throughout the subkingdom. Genetic analyses of basement membrane components in C. elegans have provided insights into their assembly and functions during development. Immuno- or GFP-tagged localization studies have shown that basement membranes on different tissues, or even sub-regions of tissues, contain different sets of proteins or alternatively spliced isoforms of them. Several components, including laminin, perlecan, type IV collagen and possibly osteonectin/SPARC, are essential for completion of embryogenesis, being necessary for tissue organization and structural integrity. In contrast, type XVIII collagen and nidogen are not required for viability but primarily influence organization of the nervous system. All of these proteins, with the exception of nidogen and the addition of fibulin, have roles of varying degree in morphogenesis of the gonad. A major family of cellular receptors for basement membrane proteins, the integrins, have also been characterized in C. elegans. As one might expect, integrins have been shown to function in many of the same processes as their potential ligands, the basement membrane components. While much remains to be explored, studies of basement membranes in C. elegans have been highly informative and hold great promise for improving our understanding of how these structures are assembled and how they function in development.
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[
WormBook,
2008]
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.