New C. elegans studies imply that lipases and lipid desaturases can mediate signaling effects on aging. But why might fat homeostasis be critical to aging? Could problems with fat handling compromise health in nematodes as they do in mammals? The study of signaling pathways that control longevity could provide the key to one of the great unsolved mysteries of biology: the mechanism of aging. But as our view of the regulatory pathways that control aging grows ever clearer, the nature (...) of aging itself has, if anything, grown more obscure. In particular, focused investigations of the oxidative damage theory have raised questions about an old assumption: that a fundamental cause of aging is accumulation of molecular damage. Could fat dyshomeostasis instead be critical? (shrink)

One of the goals in developmental biology is the identification of key regulatory genes that govern the transition of embryonic cells from a pluripotent potential to a specific, committed cell fate. During vertebrate skeletal myogenesis, this transition is regulated by the MyoD family of genes. C. elegans has muscle analogous to vertebrate skeletal muscle and has a gene(hlh‐1) related to the MyoD family. The molecular and genetic characterization of hlh‐1 shows that it is very similar to the vertebrate MyoD (...) family in many respects, including its expression pattern and DNA binding activity. The hlh‐1 product is required for proper myogenesis, but it is not required for myogenic commitment during embryogenesis in the nematode. The role of this MyoD‐related gene in nematode myogenesis is discussed and compared to those of the vertebrate MyoD family. (shrink)

The sense of touch informs us of the physical properties of our surroundings and is a critical aspect of communication. Before touches are perceived, mechanical signals are transmitted quickly and reliably from the skin's surface to mechano‐electrical transduction channels embedded within specialized sensory neurons. We are just beginning to understand how soft tissues participate in force transmission and how they are deformed. Here, we review empirical and theoretical studies of single molecules and molecular ensembles thought to be involved in mechanotransmission (...) and apply the concepts emerging from this work to the sense of touch. We focus on the nematode Caenorhabditis elegans as a well‐studied model for touch sensation in which mechanics can be studied on the molecular, cellular, and systems level. Finally, we conclude that force transmission is an emergent property of macromolecular cellular structures that mutually stabilize one another. (shrink)

A recent report by Blumenthal et al.1 provides convincing evidence that at least 15% of Caenorhabditis elegans genes are co‐transcribed within over a thousand operons. Polycistronic transcription of gene clusters is very rare in eukaryotes. The widespread occurrence of operons in C. elegans thus raises some interesting questions about the origin and function of these multigenic transcriptional units. BioEssays 24:983–987, 2002. © 2002 Wiley‐Periodicals, Inc.

During the past decade, it has become apparent that it is within our grasp to understand fully the development and functioning of complex organisms. It is widely accepted that this undertaking must include the elucidation of the genetic blueprint – the genome sequence – of a number of model organisms. As a prelude to the determination of these sequences, clonebased physical maps of the genomes of a number of multicellular animals and plants are being constructed. Yeast artificial chromosome (YAC) vectors, (...) by virtue of their relatively unbiased cloning capabilities and capacity to carry large inserts, have come to play a central role in the construction of these maps. The application of YACs to the physical map of the Caenorhabditis elegans genome has enabled cosmid clone ‘islands’ to be linked together in an efficient manner. The long‐range continuity has improved the linkage between the genetic and physical maps, greatly increasing its utility. Since the genome can be represented by a relatively small number of YACs, it has been possible to make replica filters of genomically ordered YACs available to the community at large. (shrink)

Caenorhabditis elegans (C. elegans) is a tiny worm that has become the focus of a large number of worldwide research projects examining its genetics, development, neuroscience, and behavior. Recently several groups of investigators have begun to tie together the behavior of the organism and the underlying genes, neural circuits, and molecular processes implemented in those circuits. Behavior is quintessentially organismal--it is the organism as a whole that moves and mates--but the explanations are devised at the molecular and neurocircuit (...) levels, and tested in populations using protocols that span many levels of aggregation. Following a brief review of the main relevant features of C. elegans, I describe some of these circuits, and then discuss two contrasting approaches in behavioral genetics and neural network analysis of the worm. Finally, I outline the rudiments of a "field and focus" explanation model using the two contrasting approaches. (shrink)

Understanding how biological organisms are autonomous—maintain themselves far from equilibrium through their own activities—requires understanding how they regulate those activities. In multicellular animals, such control can be exercised either via endocrine signaling through the vasculature or via neurons. In C. elegans this control is exercised by a well-delineated relatively small but distributed nervous system that relies on both chemical and electric transmission of signals. This system provides resources to integrate information from multiple sources as needed to maintain the organism. (...) Especially important for the exercise of neural control are neuromodulators, which we present as setting agendas for control through more traditional electrical signaling. To illustrate how the C. elegans nervous system integrates multiple sources of information in controlling activities important for autonomy, we focus on feeding behavior and responses to adverse conditions. We conclude by considering how a distributed nervous system without a centralized controller is nonetheless adequate for autonomy. (shrink)

Sex determination in most organisms involves a simple binary fate choice between male or female development; the outcome of this decision has profound effects on organismal biology, biochemistry and behaviour. In the nematode C. elegans, there is also a binary choice, either male or hermaphrodite. In C. elegans, distinct genetic pathways control somatic and germline sexual cell fate. Both pathways share a common set of globally acting regulatory genes; however, germline-specific regulatory genes also participate in the decision to (...) make male or female gametes. The determination of sexual fate in the germline of the facultative hermaphrodite poses a special problem, because first sperm then oocytes are produced. It has emerged that additional layers of post-transcriptional regulation have been imposed to modulate the activities of the global sex-determining genes, tra-2 and fem-3; the balance between these activities is crucial in controlling sexual cell fate in the hermaphrodite germline. BioEssays 23:596–604, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Recent findings suggest that C. elegans, albeit displaying an invariant cell lineage for embryonic development, uses the same basic strategy for embryogenesis as other organisms. The early embryo is regionalised by cell‐cell interactions.

Wnt glycoproteins are signaling molecules that control a wide range of developmental processes in organisms ranging from the simple metazoan Hydra to vertebrates. Wnt signaling also plays a key role in the development of the nematode C. elegans, and is involved in cell fate specification and determination of cell polarity and cell migration. Surprisingly, the first genetic studies of Wnt signaling in C. elegans revealed major differences with the established (canonical) Wnt signaling pathways of Drosophila and vertebrates. Thus, (...) the Wnt-dependent induction of endoderm in the early embryo and the specification of several asymmetric cell divisions during larval development are mediated by as yet novel Wnt signaling pathways that repress, rather than activate the TCF/LEF-1 transcription factor POP-1. Recently, however, it has been shown that, in addition to these divergent Wnt pathways, C. elegans also has a canonical Wnt pathway that converts POP-1 into an activator and controls the expression of several homeobox genes. Interestingly, these different Wnt pathways use distinct beta-catenins to control POP-1 function: the endoderm induction pathway requires the beta-catenin WRM-1 and parallel input from a mitogen-activated kinase (MAPK) pathway to downregulate POP-1, whereas the canonical Wnt pathway employs the beta-catenin BAR-1 to activate Wnt target gene expression. (shrink)

Heterotrimeric G proteins, consisting of α, β, and γ subunits, couple ligand-bound seven transmembrane domain receptors to the regulation of effector proteins and production of intracellular second messengers. G protein signaling mediates the perception of environmental cues in all higher eukaryotic organisms, including yeast, Dictyostelium, plants, and animals. The nematode Caenorhabditis elegans is the first animal to have complete descriptions of its cellular anatomy, cell lineage, neuronal wiring diagram, and genomic sequence. In a recent paper, Jansen et al.(1) used (...) sequence searches of the C. elegans genome database to identify all heterotrimeric G protein genes (20 Gα, 2 Gβ, 2 Gγ). C. elegans encodes one ortholog of each of the four Gα classes found in metazoans and 16 new Gα genes. The orthologous genes are widely expressed, whereas 14 of the divergent Gα genes are almost exclusively expressed in sensory neurons where they may regulate perception and chemotaxis.BioEssays 21:713–717, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

The cell division and differentiation events that occur during the development of the nematode Caenorhabditis elegans are nearly identical between different individuals, a feature that distinguishes this organism from larger and more complex metazoans, such as humans and Drosophila. In view of this discrepancy, it might be expected that the regulation of cell growth, division and differentiation in C. elegans would involve mechanisms separate from those utilized in larger animals. However, the results of recent genetic, molecular and cellular (...) studies indicate that C. elegans employs an arsenal of developmental regulatory mechanisms quite similar to those wielded by its arthropod and vertebrate relatives. Thus, the nematode system is providing both novel and complementary insights into the general problem of how growth and patterning events are integrated in development. This review offers a general perspective on the regulation of cell division and growth in C. elegans, emphasizing recent studies of these crucial aspects of development. BioEssays 24:38–53, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

Caenorhabditis elegans is a tiny worm that has become the focus of a large number of worldwide research projects examining its genetics, development, neuroscience, and behavior. Recently several groups of investigators have begun to tie together the behavior of the organism and the underlying genes, neural circuits, and molecular processes implemented in those circuits. Behavior is quintessentially organismal—it is the organism as a whole that moves and mates—but the explanations are devised at the molecular and neurocircuit levels, and tested (...) in populations using protocols that span many levels of aggregation. Following a brief review of the main relevant features of C. elegans, I describe some of these circuits, and then discuss two contrasting approaches in behavioral genetics and neural network analysis of the worm. Finally, I outline the rudiments of a “field and focus” explanation model using the two contrasting approaches. (shrink)

Heterotrimeric G proteins, consisting of α, β, and γ subunits, couple ligand-bound seven transmembrane domain receptors to the regulation of effector proteins and production of intracellular second messengers. G protein signaling mediates the perception of environmental cues in all higher eukaryotic organisms, including yeast, Dictyostelium, plants, and animals. The nematode Caenorhabditis elegans is the first animal to have complete descriptions of its cellular anatomy, cell lineage, neuronal wiring diagram, and genomic sequence. In a recent paper, Jansen et al.(1) used (...) sequence searches of the C. elegans genome database to identify all heterotrimeric G protein genes (20 Gα, 2 Gβ, 2 Gγ). C. elegans encodes one ortholog of each of the four Gα classes found in metazoans and 16 new Gα genes. The orthologous genes are widely expressed, whereas 14 of the divergent Gα genes are almost exclusively expressed in sensory neurons where they may regulate perception and chemotaxis.BioEssays 21:713–717, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

The dauer larva is a specialized third‐larval stage of Caenorhabditis elegans that is long‐lived and resistant to environmental insult. The dauer larva is formed in response to a high external concentration of a constitu‐tively secreted pheromone. Response to the dauer‐inducing pheromone of C. elegans is a promising genetic model for metazoan chemosensory transduction. More than 20 genes have been identified that are required for normal pheromone response. The functions of these genes include production of the pheromone, exposure of (...) sensory neuron endings to the environment, structural and functional integrity of those sensory endings, and the capacity of sensory neurons to make appropriate output. Genetic evidence suggests that two partially redundant sensory pathways act in concert to control dauer formation. At least two classes of chemosensory neurons, ADF and ASI, are implicated in the pheromone response. On the basis of on these findings, a speculative model for the pheromone response is proposed. In this model, the neurons ADF and ASI are pheromone sensors that repress dauer formation in the absence of pheromone and dere‐press dauer formation in response to pheromone. It is currently unclear whether or not the two genetically defined sensory pathways both act in ADF and ASI. (shrink)

Cell communication is crucial for many aspects of growth and differentiation during the development of the nematode Caenorhabditis elegans. Two genes, glp‐1 and lin‐12, mediate a number of known cell–cell interactions. Genetic and molecular analyses of these two genes lead to the conclusion that they are structurally and functionally related. We summarize these studies as well as those involving the identification of other genes that interact with glp‐1 and / or lin‐12.

Vulval development in the Caenorhabditis elegans hermaphrodite represents a simple, genetically tractable system for studying how cell signaling events control cell fata decisions. Current models suggest that proper specification of vulval cell fates relies on the integration of multiple signaling systems, including one that involves a receptor tyrosine kinase (RTK)→Ras→mitogen activated protein kinase (MAPK) cascade and one that involves a LIN‐12/Notch family receptor. In this review, we first discuss how genetic strategies are being used to identify and analyze components (...) that control vulval cell fate decisions. We then describe the different signaling systems that have been elucidated and how they relate to one another. Finally, we highlight several recently characterized genes that encode positive regulators, negative regulators or potential targets of the RTK→Ras→MAPK cascade involved in vulval induction. (shrink)

During embryogenesis, the basic axon scaffold of the nervous system is formed by special axons that pioneer pathways between groups of cells. To find their way, the pioneer growth cones detect specific cues in their extracellular environment. One of these guidance cues is netrin. Observations and experimental manipulations in vertebrates and nematodes have shown that netrin is a bifunctional guidance cue that can simultaneously attract and repel axons. During the formation of this basic axon scaffold in Caenorhabditis elegans, the (...) netrin UNC‐6 is expressed by neuroglia and pioneer neurons, providing hierarchical guidance cues throughout the animal. Each cue has a characteristic role depending on the cell type, its position and the developmental stage. These roles include activities as global, decussation and labeled‐pathway cues. This hierarchical model of UNC‐6 netrin‐mediated guidance suggests a method by which guidance cues can direct formation of basic axon scaffolds in developing nervous systems. (shrink)

Genetic and molecular studies of development in Caenorhabiditis elegans have identified regulators that appear to control pattern formation in the cellularized nematode embryo. Two genes, skn‐1 and pie‐1, are required for specifying the different identities of two sister blastomeres in a 4‐cell embryo, called P2 and EMS. The skn‐1 gene encodes a DNA binding protein that may control blastomere development by regulating transcription in EMS and its descendants. ABa and ABp, the other two sisters in a 4‐cell embryo, are (...) influenced to develop differently by cell signaling events that require the two genes apx‐1 and glp‐1. In this review, I summarize evidence that some or all of these genes may encode embryonic determinants of blastomere identity. (shrink)

Predicting the phenotype of an organism from its genotype is a central question in genetics. Most importantly, we would like to find out if the perturbation of a single gene may be the cause of a disease. However, our current ability to predict the phenotypic effects of perturbations of individual genes is limited. Network models of genes are one tool for tackling this problem. In a recent study, (Lee et al.) it has been shown that network models covering the majority (...) of genes of an organism can be used for accurately predicting phenotypic effects of gene perturbations in multicellular organisms. BioEssays 30:707–710, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Physical contact between organelles are widespread, in part to facilitate the shuttling of protein and lipid cargoes for cellular homeostasis. How do protein‐protein and protein‐lipid interactions shape organelle subdomains that constitute contact sites? The endoplasmic reticulum (ER) forms extensive contacts with multiple organelles, including lipid droplets (LDs) that are central to cellular fat storage and mobilization. Here, we focus on ER‐LD contacts that are highlighted by the conserved protein seipin, which promotes LD biogenesis and expansion. Seipin is enriched in ER (...) tubules that form cage‐like structures around a subset of LDs. Such enrichment is strongly dependent on polyunsaturated and cyclopropane fatty acids. Based on these findings, we speculate on molecular events that lead to the formation of seipin‐positive peri‐LD cages in which protein movement is restricted. We hypothesize that asymmetric distribution of specific phospholipids distinguishes cage membrane tubules from the bulk ER. (shrink)

Developmental biology has resurfaced in recent years, often without a clearly central role for the organism. The organism is pulled in divergent directions: on the one hand, there is an important body of work that emphasizes the role of the gene in development, as executing and controlling embryological change; on the other hand, there are more theoretical approaches under which the organism disappears as little more than an instance for testing biological generalizations. I press here for the ineliminability of the (...) organism in developmental biology on explanatory grounds. I examine classical work concerned with growth and development, particularly in Drosophila and C. elegans. Some of this work is suggestive of modular development, and accordingly suggests a level below that of the organism as being explanatory. These are not the only type of case. There are other equally well-established results, which indicate greater integration in the developing organism. Though with a modular organization the organism can be thought of as made up of its constituent traits, and though the explanations of these traits may lie in terms of cells or genes, even with modular development the explanations of "genetic" differences require an appeal to the organism. With non-modular organization the organism has an even more central role. This does not mean that these genetic or cellular contributions are unreal in any way, or that development requires some sort of vitalistic contribution; but the genetic contributions make sense only as constituents of the organism, embedded in a larger organic context. (shrink)

During development one mechanism for generating different cell types is asymmetric cell division, by which a cell divides and contributes different factors to each of its daughter cells. Asymmetric cell division occurs through out the eukaryotic kingdom, from yeast to humans. Many asymmetric cell divisions occur in a defined orientation. This implies a cellular mechanism for sensing direction, which must ultimately lead to differences in gene expression between two daughter cells. In this review, we describe two classes of molecules: regulatory (...) factors that are differentially expressed upon asymmetric cell division, and components of a signal transduction pathway that may define cell polarity. The lin‐11 and mec‐3 genes of C. elegans, the Isl‐1 gene of mammals and the HO gene of yeast, encode regulatory factors that determine cell type of one daughter after asymmetric cell division. The CDC24 and CDC42 genes of yeast affect both bud positioning and orientation of mating projections, and thus may define a general cellular polarity. We speculate that molecules such as Cdc24 and Cdc42 may regulate expression of genes such as lin‐11, mec‐3, Isl‐1 and HO upon asymmetric cell division. (shrink)

Although the type‐I interferon (IFN‐I) response is considered vertebrate‐specific, recent findings about the Intracellular Pathogen Response (IPR) in nematode Caenorhabditis elegans indicate that there are similarities between these two transcriptional immunological programs. The IPR is induced during infection with natural intracellular fungal and viral pathogens of the intestine and promotes resistance against these pathogens. Similarly, the IFN‐I response is induced by viruses and other intracellular pathogens and promotes resistance against infection. Whether the IPR and the IFN‐I response evolved in (...) a divergent or convergent manner is an unanswered and exciting question, which could be addressed by further studies of immunity against intracellular pathogens in C. elegans and other simple host organisms. Here we highlight similar roles played by RIG‐I‐like receptors, purine metabolism enzymes, proteotoxic stressors, and transcription factors to induce the IPR and IFN‐I response, as well as the similar consequences of these defense programs on organismal development. (shrink)

In response to nutrient limitation, many animals, including Caenorhabditis elegans, slow or arrest their development. This process requires mechanisms that sense essential nutrients and induce appropriate responses. When faced with nutrient limitation, C. elegans can induce both short and long‐term survival strategies, including larval arrest, decreased developmental rate, and dauer formation. To select the most advantageous strategy, information from many different sensors must be integrated into signaling pathways, including target of rapamycin (TOR) and insulin, that regulate developmental progression. (...) Here, how nutrient information is sensed and integrated into developmental decisions that determine developmental rate and progression in C. elegans is reviewed. (shrink)

This book provides a broad survey of many of the major areas in neuroplasticity research by leading investigators in the field. The topics considered range across all levels of nervous system organization from the molecular to behavioral levels for species ranging from _C. elegans_ to humans. In addition, the effects of development and neuropathological events are discussed. A final summary chapter synthesizes the data gathered in this volume in order to provide the basis for a general theory of neuroplasticity.

The nematode C. elegans exhibits a variety of reponses to touch. When specific sets of mechanosensory neurons are killed with a laser, specific touch responses are abolished. Many mutations that result in defective mechanosensation have been identified. Some of the mutations define genes that specify the fate of a set of mechanoreceptors called the touch cells, which mediate response to light touch to the body of the worm. Genes specifying touch cell fate appear to regulate genes that encode touch‐cell (...) differentiation proteins, including apparent subunits of a touch‐cell‐specific ion channel, rare mutant forms of which lead to swelling and lysis of the touch cells. Molecular attachments of the ion channel, both to extracellular matrix components and, intracellularly, to a special large‐diameter microtubule, may be required for mechanical gating of the channel. A mechanoreceptor‐interneuron‐motorneuron reflex circuit for response to light touch has been proposed. (shrink)

The endomesoderm gene regulatory network (GRN) of C. elegans is a rich resource for studying the properties of cell‐fate‐specification pathways. This GRN contains both cell‐autonomous and cell non‐autonomous mechanisms, includes network motifs found in other GRNs, and ties maternal factors to terminal differentiation genes through a regulatory cascade. In most cases, upstream regulators and their direct downstream targets are known. With the availability of resources to study close and distant relatives of C. elegans, the molecular evolution of this (...) network can now be examined. Within Caenorhabditis, components of the endomesoderm GRN are well conserved. A cursory examination of the preliminary genome sequences of two parasitic nematodes, Haemonchus contortus and Brugia malayi, suggests that evolution in this GRN is occurring most rapidly for the zygotic genes that specify blastomere identity. BioEssays 28: 1010–1022, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

The C. elegans male tail is being studied as a model to understand how genes specify the form of multicellular animals. Morphogenesis of the specialized male copulatory organ takes place in the last larval stages during male development. Genetic analysis is facilitated because the structure is not necessary for male viability or for strain propagation. Analysis of developmental mutants, isolated in several functional and morphological screens, has begun to reveal how fates of cells are determined in the cell lineages, (...) and how the specification of cell fates affects the morphology of the structure. Cytological studies in wild type and in mutants have been used to study the mechanism of pattern formation in the tail peripheral nervous system. The ultimate goal is to define the entire pathway leading to the male copulatory organ. (shrink)

Graphical AbstractNowadays, in the Internet databases era, certain knowledge is being progressively lost. This knowledge, which we feel is essential and should be acquired through education, is the understanding of how the pioneer researchers faced major questions in their field and made their discoveries.

This study focuses on the concept of a 'model organism' in the biomedical sciences through an historical and philosophical examination of research with the nematode Caenorhabditis elegans. I explore the choice of C. elegans in the mid-1960s, showing a rich context existed within which the organism was selected as the focus for a molecular biological research program, including an experimental life prior to Sydney Brenner's work. I argue that this choice can be seen as an obvious outcome of (...) what was a complex search procedure, and that the success of the 'worm project' depended not only on organismal choice but also on the conceptual and institutional framework at the Laboratory of Molecular Biology in Cambridge within which it was pursued. Examination of C. elegans work in the late 1960s through the early 1980s illuminates several additional theses. Although development and behavior were the general areas of interest for the project, the original goals and proposed methodology were extremely vague. As the project evolved, which investigations proved to be tractable using the worm depended not only on which methodologies were fruitful but also on the interests and skills of early workers. Much of the power of C. elegans as a model organism can be traced historically to the investment of resources which resulted in an unprecedented, complete description of the organism, and represented a return to a more naturalistic biological tradition. In light of the historical study, I develop a philosophical analysis of C. elegans as a model organism through exploration of the three kinds of modeling with the worm: modeling of structures, processes, and information. I expand the notion of a descriptive model, arguing that C. elegans is best understood as a prototype of the metazoa, and that C. elegans as a model organism has been not only heuristically valuable, but also essential to this research project particularly in its pre-explanatory stages. I conclude by suggesting that more investigation of descriptive prototypes such as those in the worm project must be done to capture important aspects of the biomedical sciences that will be neglected if explanatory models are the sole focus in the philosophy of science. (shrink)

Chemotaxis and thermotaxis in Caenorhabditis elegans are based on the chemical senses (smell and taste) and the thermal sense, respectively, which are important for the life of the animal. Laser ablation experiments have allowed identification of sensory neurons and some interneurons required for these senses. Many mutants that exhibit various abnormalies have been isolated and analyzed. These studies have predicted novel signaling pathways whose components include a putative odorant specific transmembrane receptor (ODR‐10) and a cyclic nucleotide‐gated channel (TAX‐4/TAX‐2) functioning (...) in taste and thermosensation as well as in smell. The emerging picture of the mechanisms of sensory transduction in C. elegans seems to be basically similar to what is known of visual and olfactory sensory transduction in vertebrates. Thus, molecular and cellular analyses of chemotaxis and thermotaxis in C. elegans have proved useful and will continue to provide significant implications for the molecular basis of sensory systems in higher animals. (shrink)

The cuticle of the nematode Caenorhabditis elegans forms the barrier between the animal and its environment. In addition to being a protective layer, it is an exoskeleton which is important in maintaining and defining the normal shape of the nematode. The cuticle is an extracellular matrix consisting predominantly of small collagen‐like proteins that are extensively crosslinked. Although it also contains other protein and non‐protein compounds that undoubtedly play a significant part in its function, the specific role of collagen in (...) cuticle structure and morphology is considered here. The C. elegans genome contains between 50 and 150 collagen genes, most of which are believed to encode cuticular collagens. Mutations that result in cuticular defects and grossly altered body form have been identified in more than 40 genes. Six of these genes are now known to encode cuticular collagens, a finding that confirms the importance of this group of structural proteins to the formation of the cuticle and the role of the cuticle as an exoskeleton in shaping the worm. It is likely that many more of the genes identified by mutations giving altered body form, will be collagen genes. Mutations in the cuticular collagen genes provide a powerful tool for investigating the mechanisms by which this group of proteins interact to form the nematode cuticle. (shrink)

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. BioEssays 26:39–49, 2004.© 2003 Wiley Periodicals, Inc. (shrink)

Growth factor receptor tyrosine kinases (RTKs), such as the fibroblast growth factor receptor (FGFR), play a major role in how cells communicate with their environment. FGFR signaling is crucial for normal development, and its misregulation in humans has been linked to developmental abnormalities and cancer. The precise molecular mechanisms by which FGFRs transduce extracellular signals to effect specific biologic responses is an area of intense research. Genetic analyses in model organisms have played a central role in our evolving understanding of (...) these signal transduction cascades. Genetic studies in the nematode C. elegans have contributed to our knowledge of FGFR signaling by identifying genes involved in FGFR signal transduction and linking their gene products together into signaling modules. This review will describe FGFR-mediated signal transduction in C. elegans and focus on how these studies have contributed to our understanding of how FGFRs orchestrate the assembly of intracellular signaling pathways. BioEssays 23:1120–1130, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Chromosome ends have been implicated in the meiotic processes of the nematode Caenorhabditis elegans. Cytological observations have shown that chromosome ends attach to the nuclear membrane and adopt kinetochore functions. In this organism, centromeric activity is highly regulated, switching from multiple spindle attachments all along the chromosome during mitotic division to a single attachment during meiosis. C. elegans chromosomes are functionally monocentric during meiosis. Earlier genetic studies demonstrated that the terminal regions of the chromosomes are not equivalent in (...) their meiotic potentials. There are asymmetries in the abilities of the ends to recombine when duplicated or deleted. In addition, mutations in single genes have been identified that mimic the meiotic effects of a terminal truncation of the X chromosome. The recent cloning and characterization of the C. elegans telomeres has provided a starting point for the study of chromosomal elements mediating the meiotic process. (shrink)

The change in shape of the C. elegans embryo from an ovoid ball of cells into a worm-shaped larva is driven by three events within the cells of the hypodermis (epidermis): (1) intercalation of two rows of dorsal cells, (2) enclosure of the ventral surface by hypodermis, and (3) elongation of the embryo. While the behavior of the hypodermal cells involved in each of these processes differs dramatically, it is clear that F-actin and microtubules have essential functions in each (...) of these processes, whereas contraction of actomyosin structures appears to be involved specifically in elongation. Molecular analysis of these processes is revealing components specific to C. elegans as well as components found in other systems. Since C. elegans hypodermal cells demonstrate dramatically different behaviors during intercalation, enclosure and elongation, the study of cytoskeletal dynamics in these processes may reveal both unique and conserved activities during distinct epithelial morphogenetic movements. BioEssays 23:12–23, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Significant advances have recently been made in our understanding of the mechanisms of activation of proteins that require processing. Often this involves endoproteolytic cleavage of precursor forms at basic residues, and is carried out by a group of serine endoproteinases, termed the proprotein convertases. In mammals, seven different convertases have been identified to date. These act in both the regulated secretory pathway for the processing of prohormones and proneuropeptides and in the constitutive secretory pathway, in which a variety of proproteins (...) are activated endoproteolytically. The recently completed sequence of the nematode Caenorhabditis elegans genome affords a unique opportunity to examine the entire proprotein convertase family in a multicellular organism. Here we review the nature of the family, emphasising the structural features, characteristic of the four nematode genes, that supply all of the necessary functions unique to this group of serine endoproteinases. Studies of the C. elegans genes not only provide important information about the evaluation of this gene family but should help to illuminate the roles of these proteins in mammalian systems. BioEssays 22:545–553, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Powerful ultrastructural tools are providing new insights into neuronal circuits, revealing a wealth of anatomically‐defined synaptic connections. These wiring diagrams are incomplete, however, because functional connectivity is actively shaped by neuromodulators that modify neuronal dynamics, excitability, and synaptic function. Studies of defined neural circuits in crustaceans, C. elegans, Drosophila, and the vertebrate retina have revealed the ability of modulators and sensory context to reconfigure information processing by changing the composition and activity of functional circuits. Each ultrastructural connectivity map encodes (...) multiple circuits, some of which are active and some of which are latent at any given time. (shrink)

Tissues are shaped and patterned by mechanical and chemical processes. A key mechanical process is the positioning of the mitotic spindle, which determines the size and location of the daughter cells within the tissue. Recent force and position-fluctuation measurements indicate that pushing forces, mediated by the polymerization of astral microtubules against­ the cell cortex, maintain the mitotic spindle at the cell center in Caenorhabditis elegans embryos. The magnitude of the centering forces suggests that the physical limit on the accuracy (...) and precision of this centering mechanism is determined by the number of pushing microtubules rather than by thermally driven fluctuations. In cells that divide asymmetrically, anti-centering, pulling forces generated by cortically located dyneins, in conjunction with microtubule depolymerization, oppose the pushing forces to drive spindle displacements away from the center. Thus, a balance of centering pushing forces and anti-centering pulling forces localize the mitotic spindles within dividing C. elegans cells. We discuss microtubule-based mechanisms of the mitotic spindle positioning, a key mechanical process that shapes and patterns tissues. The magnitude of the centering forces indicates that the physical limit on the accuracy and precision of centering is set by the number of contributing microtubules rather than by thermally driven fluctuations. (shrink)