Early embryogenesis of Caenorhabditis elegans provides a striking example of the generation of polarity and the partitioning of cytoplasmic factors according to this polarity. Microfilaments (MFs) appear to play a critical role in these processes. By visualizing the distribution of MFs and by studying the consequences of disrupting MFs for short, defined periods during zygote development, we have generated some new ideas about when and how microfilaments function in the zygote.

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)

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)

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)

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)

Development of the nematode Caenorhabditis elegans has been described completely on a cell‐by‐cell basis. In an invariant pattern five somatic founder cells and the primordial germ cell are generated within the first hour after the onset of cleavage. Using a laser microbeam for manipulation of individual blastomers several aspects of early embryogenesis have been investigated, including the expression of cellular polarity, the localization of lineage‐specific cleavage potential, the necessity for early cell–cell interaction, and the control of differential cell‐cycle (...) timing. The experiments demonstrate the central importance of a correct partitioning of cytoplasmic components during early embryogenesis and suggest a stepwise, binary segregation mechanism associated with the unequal cleavages in the germline. (shrink)

In Caenorhabditis elegans, sex is determined by the number of X chromosomes which, in turn, determines the expression of the X‐linked gene xol‐1. Recent work(1) has shown that xol‐1 expression is controlled by least two distinct regulatory mechanisms, one transcriptional and another post‐transcriptional. The transcriptional regulator is a repressor acting in XX embryos; although the specific gene has not been identified, the chromosome region has been defined. A previously defined regulator of xol‐1, known as fox‐1, maps to a (...) different region of the X chromosome and works post‐transcriptionally, consistent with the identification of the fox‐1 gene product as a putative RNA binding protein(2). (shrink)

We show how a simple nonlinear dynamical system (the discrete quadratic iteration on the unit segment) can be the basis for modelling the embryogenesis process. Such an approach, even though being crude, can nevertheless prove to be useful when looking with the two main involved processes:i) on one hand the cell proliferation under successive divisions ii) on the other hand, the differentiation between cell lineages. We illustrate this new approach in the case of Caenorhabditis elegans by looking at (...) the early stages of embryogenesis, up to several hundreds of cells (lima bean larval stage). We show how the many results that have been obtained by several groups can be interpreted in terms of values for the parameters controlling the dynamical system. Furthermore, we can extend the model to the cases of genetic mutations. More precisely the teratogenetic and lethal effects are associated with abnormal variation of the control parameters with time. (shrink)

Axon regeneration is a conserved process across the animal kingdom. Recent studies using the soil worm Caenorhabditis elegans as a model system revealed that machineries regulating engulfment of dying cells also control axon regeneration and axon debris removal. In this review, the relationships between the engulfment machinery and the biological processes triggered by axon injury and subsequent axon regeneration drawn from divergent views are examined. In one study, it is found that engulfing cells directly promote axon regeneration. In (...) this context, CED‐1 (Drosophila Draper/mouse MEGF10), an engulfment protein expressed on the surface of engulfing cells, functions as a receptor for axon debris removal and as an adhesion molecule for axon regeneration. In other studies, it is shown that those engulfment genes, previously known to function within the engulfing cells for cell corpse removal, can have a cell‐autonomous “non‐engulfing cell” role in axon regeneration. Together, these findings suggest that engulfment genes are repurposed for neuronal regeneration by acting in both engulfing cells and regenerating neurons. (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)

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)

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)

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)

Deciphering the neural basis of subjective experience remains one of the great challenges in the natural sciences. The structural complexity and the limitations around invasive experimental manipulations of the human brain have impeded progress towards this goal. While animals cannot directly report first-person subjective experiences, their ability to exhibit flexible behaviours such as motivational trade-offs are generally considered evidence of sentience. The worm _Caenorhabditis elegans_ affords the unique opportunity to describe the circuitry underlying subjective experience at a single cell level (...) as its whole neural connectome is known and moreover, these animals exhibit motivational trade-offs. We started with the premise that these worms were sentient and then sought to understand the neurons that were both necessary and sufficient for a motivational trade-off involving the rewarding experience of food and the negative experience of an aversive odour. A simple hierarchical network consisting of two chemosensory neurons and three interneurons was found to produce an output to motoneurons that enabled worms to respond in a contextually appropriate manner to an aversive odour according to the worm's hunger state. Given that this circuitry is like that found in the human spinal cord, retina, and primary visual cortex, three regions which are neither necessary nor sufficient for subjective experience, we conclude that motivational trade-offs are not a criterion for subjective experience in worms. Furthermore, once the neural substrate for a behaviour is described, we question the explanatory role of subjective experience in behaviour. (shrink)

The signal for sex determination in the nematode Caenorhabditis elegans is the ratio between the number of × chromosomes and the number of sets of autosomes (the X/A ratio). Animals with an X/A ratio of 0.67 (a triploid with two × chromosomes) or less are males. Animals with an X/A ratio of 0.75 or more are hermaphrodites. Thus, diploid males have one × chromosome and diploid hermaphrodites have two × chromosomes. However, the difference in X‐chromosome number between the (...) sexes is not reflected in general levels of X‐linked gene expression because of the phenomenon of dosage compensation. In dosage compensation, X‐linked gene expression appears to be ‘turned down’ in 2X animals to the 1X level of expression. An intriguing and unexplained finding is that mutations and X‐chromosome duplications that elevate X‐linked gene expression also feminize triploid males. One way that this relationship between sex determination and X‐linked gene expression may be operating is discussed. (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)

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)

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.

It is somewhat ironic that animals that are the prime choice for detailed genetic analysis, such as the fruit fly and the nematode, have thus far been largely refractory to reverse genetic analysis. Their detailed genetic map, and small genome size have made them subjects of ambitious genome analysis projects, but there is still no strategy to introduce desired changes into their genomes by homologous recombination. Some alternative approaches have recently become available; this review describes possibilities and unsolved problems for (...) reverse genetics in the nematode Caenorhabditis elegans. The transposon Tc1 could prove to be very useful for the isolation of knock out mutants, and possibly also for introduction of more subtle alterations. (shrink)

Analysis of the patterns of cell lineage observed during development of the nematode Caenorhabditis elegans, combined with selected cell ablation experiments, has revealed that while many cell fates are autonomously (intrinsically) determined, cell–cell interactions are required for a number of developmental decisions. Earlier genetic analysis of one key gene, lin‐12, had shown that this gene controls a number of bi‐potential fate decisions involving such cellular interactions. Molecular analysis of this gene is now providing clues to its mode of (...) action in mediating these cell‐fate decision. (shrink)

Ageing is a complex phenomenon which remains a major challenge to modern biology. Although the evolutionary biology of ageing is well understood, the mechanisms that limit lifespan are unknown. The isolation and analysis of single‐gene mutations which extend lifespan (Age mutations) is likely to reveal processes which influence ageing. Caenorhabditis elegans is the only metazoan in which Age mutations have been identified. The Age mutations not only prolong life, but also confer a complex array of other phenotypes. Some (...) of these phenotypes provide clues to the evolutionary origins of these genes while others allude to mechanisms of lifespan‐extension. Many of the Age genes interact and share a second common phenotype, that of stress resistance. Rather than invertebrate ageing being determined by a ‘clock mechanism’, a picture is emerging of ageing as a non‐adaptive process determined, in part, by resistance to intrinsic stress mediated by stress‐response genes. (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)

In eukaryotes, double‐stranded RNAs (dsRNAs) or short, interfering dsRNAs (siRNAs) can reduce the accumulation of a sequence‐related mRNA, often resulting in a loss‐of‐function phenotype—a process termed RNA interference (RNAi). Unfortunately, some mRNAs are resistant to the effects of dsRNA. Experiments designed to unravel RNAi mechanisms in Caenorhabditis elegans have led to the identification of two worm proteins, RRF‐31,2 and, now, ERI‐1,3 that can inhibit RNAi responses. Animals defective in either protein can display enhanced RNAi phenotypes for mRNAs that (...) were previously resistant to dsRNA. Since ERI‐1 is a conserved protein, development of procedures to enhance RNAi effectiveness in other systems may be possible. BioEssays 26:715–718, 2004. © 2004 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)

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)

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)

One important aspect of biological explanation is detailed causal modeling of particular phenomena in limited experimental background conditions. Recognising this allows one to appreciate that a sufficient condition for a reduction in biology is a molecular model of (1) only the demonstrated causal parameters of a biological model and (2) only within a replicable experimental background. These identities—which are ubiquitous in biology and form the basis of ruthless reductions (Bickle, Philosophy and neuroscience: a ruthlessly reductive account, 2003)—are criticised as merely (...) “local” (Sullivan, Synthese 167:511–539, 2009) or “fragmentary” (Schaffner, Synthese, 151(3):377–402, 2006). However, in an instructive case, a biological model is preserved in molecular terms, demonstrating a complex phenomenon that has been successfully reduced. (shrink)

Recent research has filled many gaps about Caenorhabditis natural history, simultaneously exposing how much remains to be discovered. This awareness now provides means of connecting ecological and evolutionary theory with diverse biological patterns within and among species in terms of adaptation, sexual selection, breeding systems, speciation, and other phenomena. Moreover, the heralded laboratory tractability of C. elegans, and Caenorhabditis species generally, provides a powerful case study for experimental hypothesis testing about evolutionary and ecological processes to levels of (...) detail unparalleled by most study systems. Here, I synthesize pertinent theory with what we know and suspect about Caenorhabditis natural history for salient features of biodiversity, phenotypes, population dynamics, and interactions within and between species. I identify topics of pressing concern to advance Caenorhabditis biology and to study general evolutionary processes, including the key opportunities to tackle problems in dispersal dynamics, competition, and the dimensionality of niche space. (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)

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)

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)

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.

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)

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)

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)

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)

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.

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)

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)

Small GTPases in the Rho family act as major nodes with functions beyond cytoskeletal rearrangements shaping the Caenorhabditis elegans embryo during development. These small GTPases are key signal transducers that integrate diverse developmental signals to produce a coordinated response in the cell. In C. elegans, the best studied members of these highly conserved Rho family small GTPases, RHO‐1/RhoA, CED‐10/Rac, and CDC‐42, are crucial in several cellular processes dealing with cytoskeletal reorganization. In this review, we update the functions (...) described for the Rho family small GTPases in spindle orientation and cell division, engulfment, and cellular movements during C. elegans embryogenesis, focusing on the Rho subfamily Rac.Please also see the video abstract here. (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)

Although Caenorhabditis elegans was chosen and modified to be an organism that would facilitate a reductionist program for neurogenetics, recent research has provided evidence for properties that are emergent from the neurons. While neurogenetic advances have been made using C. elegans which may be useful in explaining human neurobiology, there are severe limitations on C. elegans to explain any significant human behavior.

Although developmental biology is an institutionalized discipline, no unambiguous account of what development is and when it stops has so far been provided. In this article, I focus on two sets of developmental molecular mechanisms, namely those underlying the heterochronic pathway in C. elegans and those involving Hox genes in vertebrates, to suggest a conceptual account of animal development. I point out that, in these animals, the early stages of life exhibit salient mechanistic features, in particular in the way (...) mechanisms of genetic regulation occur in the organism. Indeed, these stages are characterized by sequential and irreversible changes in gene expression taking place throughout the organism. A general definition of animal development based on these distinctive features implies that, at least for some animal species, development does not go on throughout the life of the animal, contrary to what has recently been claimed by some biologists and philosophers. Instead, in such species, development encompasses various events occurring sequentially at the beginning of life. (shrink)

Invertebrate genetic models with their tractable neuromuscular systems are effective vehicles for the study of human nerve and muscle disorders. This is exemplified by insights made into spinal muscular atrophy (SMA) using the fruit fly Drosophila melanogaster and the nematode worm Caenorhabditis elegans. For speed and economy, these invertebrates offer convenient, whole‐organism platforms for genetic screening as well as RNA interference (RNAi) and chemical library screens, permitting the rapid testing of hypotheses related to disease mechanisms and the exploration (...) of new therapeutic routes and drug candidates. Here, we discuss recent developments encompassing synaptic physiology, RNA processing, and screening of compound and genome‐scale RNAi libraries, showcasing the importance of invertebrate SMA models.Editor's suggested further reading in BioEssays: SMN and Gemins: ‘We are family’... or are we? Abstract. (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)

Acute starvation can have long-term consequences that are mediated through epigenetic change. Some of these changes are affected by the activity of AMP-activated protein kinase, a master regulator of cellular energy homeostasis. In Caenorhabditis elegans, the absence of AMPK during a period of starvation in an early larval stage results in developmental defects following their recovery on food, while many of them become sterile. Moreover, the loss of AMPK during this quiescent period results in transgenerational phenotypes that can (...) become progressively worse with each successive generation. Our recent data describe a chromatin-based mechanism of how AMPK mediates adjustment to acute starvation in the germ cells, however, the heritable aspect of this AMPK mutant phenotype remains unresolved. Here, we explore how AMPK might affect this process and speculate how the initial transcription that occurs in the germ cells may adversely affect subsequent germline gene expression and/or genomic integrity. AMPK protects germ cell integrity during acute starvation by blocking inappropriate transcription. How these aberrant transcripts cause transgenerational defects is unclear. AMPK likely regulates germline integrity at multiple levels through several targets. The authors speculate here how AMPK disruption during starvation could result in the observed defects seen at each generation. (shrink)

Our understanding of biological processes in humans is often based on examination of analogous processes in other organisms. The nematode worm Caenorhabditis elegans has been a particularly valuable model, leading to Nobel prize winning discoveries in development and genetics. Until recently, however, the worm has not been widely used as a model to study transcription due to the lack of a comprehensive catalogue of its RNA transcripts. A recent study by Chen et al. uses next‐generation sequencing to address (...) this issue, mapping the transcription initiation sites in C. elegans and finding many unexpected similarities between the transcription of enhancers and promoters in the worm and mammalian genomes. As well as providing a valuable resource for researchers in the C. elegans community, these findings raise the possibility of using the worm as a model to investigate some key, current questions about transcriptional regulation that remain technically challenging in more complex organisms. (shrink)

Several general anesthetics produce their sedative effect by activating endogenous sleep pathways. We propose that general anesthesia is a two‐step process targeting sleep circuits at low doses, and synaptic release mechanisms across the entire brain at the higher doses required for surgery. Our hypothesis synthesizes data from a variety of model systems, some which require sleep (e.g. rodents and adult flies) and others that probably do not sleep (e.g. adult nematodes and cultured cell lines). Non‐sleeping systems can be made insensitive (...) (or hypersensitive) to some anesthetics by modifying a single pre‐synaptic protein, syntaxin1A. This suggests that the synaptic release machinery, centered on the highly conserved SNARE complex, is an important target of general anesthetics in all animals. A careful consideration of SNARE architecture uncovers a potential mechanism for general anesthesia, which may be the primary target in animals that do not sleep, but a secondary target in animals that sleep. (shrink)