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Adaptive developmental plasticity is a common phenomenon across diverse organisms and allows a single genotype to express multiple phenotypes in response to environmental signals. Developmental plasticity is thus thought to reflect a key adaptation to cope with heterogenous habitats. Adaptive plasticity often relies on highly regulated processes in which organisms sense environmental cues predictive of unfavourable environments. The integration of such cues may involve sophisticated neuro-endocrine signaling pathways to generate subtle or complete developmental shifts. A striking example of adaptive plasticity is found in the nematode C. elegans, which can undergo two different developmental trajectories depending on the environment. In favourable conditions, C. elegans develops through reproductive growth to become an adult in three days at 20 °C. In contrast, in unfavourable conditions (high population density, food scarcity, elevated temperature) larvae can adopt an alternative developmental stage, called dauer. dauer larvae are highly stress-resistant and exhibit specific anatomical, metabolic and behavioural features that allow them to survive and disperse. In C. elegans, the sensation of environmental cues is mediated by amphid ciliated sensory neurons by means of G-coupled protein receptors. In favourable environments, the perception of pro-reproductive cues, such as food and the absence of pro-dauer cues, upregulates insulin and TGF-β signaling in the nervous system. In unfavourable conditions, pro-dauer cues lead to the downregulation of insulin and TGF-β signaling. In favourable conditions, TGF-β and insulin act in parallel to promote synthesis of dafachronic acid (DA) in steroidogenic tissues. Synthetized DA binds to the DAF-12 nuclear receptor throughout the whole body. DA-bound DAF-12 positively regulates genes of reproductive development in all C. elegans tissues. In poor conditions, the inhibition of insulin and TGF-β signaling prevents DA synthesis, thus the unliganded DAF-12 and co-repressor DIN-1 repress genes of reproductive development and promote dauer formation. Wild C. elegans have often been isolated as dauer larvae suggesting that dauer formation is very common in nature. Natural populations of C. elegans have colonized a great variety of habitats across the planet, which may differ substantially in environmental conditions. Consistent with divergent adaptation to distinct ecological niches, wild isolates of C. elegans and other nematode species isolated from different locations show extensive variation in dauer induction. Quantitative genetic and population-genomic approaches have identified many quantitative trait loci (QTL) associated with differences in dauer induction as well as a few underlying causative molecular variants. In this review, we summarize how C. elegans dauer formation is genetically regulated and how this trait evolves- both within and between species., (© Société de Biologie, 2020.)

During the last decade, studies aimed at investigating genes and molecular pathways involved in aging have been very fruitful and led to the identification of several mechanisms responsible for aging. Overall, those results put forward the capacity of cells and organisms to sense and respond to stress, as a critical factor for a healthy and long life. Those molecular pathways are tightly linked with the overall metabolism of an organism. Indeed, environmental stresses trigger a plethora of defense mechanisms which are energy demanding while still the organism has to allocate energy for the maintenance of basic functions. So all along our life, we have to adapt to different stresses while optimizing energy use. This review aims at highlighting data from the literature that support the crucial role of metabolism as a modulator of aging and age-associated disease, as illustrated by the beneficial effect of dietary restriction on longevity and cancer development., (© 2012 médecine/sciences – Inserm / SRMS.)

Interindividual variation, be it of environmental or genetic origin, is crucial for biological evolution as well as in the medical context. This variation is not always directly visible, yet may be revealed under some environmental or genetic condition. In this essay is presented the example of the developmental model system underlying vulva formation in the nematode Caenorhabditis elegans, where an intercellular signaling network (EGF-Ras-MAP kinase, Notch and Wnt pathways) is involved in spatial patterning of the fates of the vulva precursor cells. Variation may be studied at two levels: (1) rare deviations in the system's output, i.e. the spatial pattern of vulva precursor cell fates ; (2) so-called << cryptic >> variation in the underlying intercellular signaling network, without change in the system's output. Like every biological system, this network displays genetic and -environmental epistasis.

The nematode Caenorhabditis elegans has evolved as a powerful invertebrate model to study innate immunity to pathogens. C. elegans possesses inducible defence mechanisms to protect itself from pathogenic attack, mainly by the production of antimicrobial effector molecules. Its innate immune system is under the control of a surprisingly complex network of evolutionary conserved signalling pathways, which are activated depending on the pathogen, suggesting that C. elegans is able to mount a specific defence response to different pathogens. In this review we will introduce the worm's immune system and discuss the different signalling pathways that regulate its response to bacterial pathogens which mainly infect C. elegans by an oral route and by invading its intestine, before focusing our attention on the resistance of C. elegans to a natural occurring fungal -pathogen that infects the worm by invading its -epidermis.

Numerous evidences indicate that the phenotype of a neurodegenerative disease and its pathogenetic mechanism are only loosely linked. The phenotype is directly related to the topography of the lesions and is reproduced whatever the mechanism as soon as the same neurons are destroyed or deficient: the symptoms of Parkinson disease are mimicked by any destruction of the neurons of the substantia nigra, caused for instance by the toxin MPTP. This does not mean that idiopathic Parkinson disease is due to MPTP. In the same way, mouse lines such as Reeler, Weaver and Staggerer in which ataxia occurs spontaneously does not help to understand human ataxias: now that mutations responsible for these phenotypes have been identified, it appears that one is responsible for lissencephaly (mutation of the reelin gene) and the other two have no equivalent in man. Therapeutic attempts, however, rely on the understanding of the pathogenetic mechanisms. Introducing a mutated human transgene in the genome of an animal has, in many instances, significantly improved this understanding. Transgenic mice have proven useful in reproducing lesions seen in neurodegenerative disease such as the plaques of Alzheimer disease (in the APP mouse which has integrated the mutated gene of the amyloid protein precursor), the tau glial and neuronal accumulation (seen in cases of frontotemporal dementias due to tau mutation), the nuclear inclusions caused by CAG triplet expansion (seen in the mutation of Huntington disease and autosomal dominant spinocerebellar ataxias). These recent advances have fostered numerous therapeutic attempts. Transgenesis in drosophila and in the worm Caenorhabditis elegans have opened new possibilities in the screening of protein partners, modifier genes, and potential therapeutic molecules. However, it is also becoming clear that introducing a human mutated gene in an animal does not necessarily trigger pathogenetic cascades identical to those seen in the human disease. Human diseases have to be studied in parallel with their animal models to ensure that the model mimic at least a few original mechanisms, on which new therapeutics may be tested.

The Nematode Caenorhabditis elegans (C. elegans) is an established model increasingly used for studying human disease pathogenesis. C. elegans models are based on the mutagenesis of human disease genes conserved in this Nematode or on the transgenesis with disease genes not conserved in C. elegans. Genetic examinations will give new insights on the cellular and molecular mechanisms that are altered in some neurodegenerative diseases like Duchenne's muscular dystrophy, Huntington's disease and Alzheimer's disease. C. elegans may be used for primary screening of new compounds that may be used as drugs in these diseases.

"Nothing in biology makes sense except in the light of evolution", wrote Theodosius Dobzhansky, one of the founders of the Modern Synthesis that led to the unification of evolutionary theory and genetics in the midst of the 20th century. Programmed cell death is a genetically regulated process of cell suicide that is central to the development, homeostasis and integrity of multicellular organisms. Conversely, the dysregulation of mechanisms controlling cell suicide plays a role in the pathogenesis of a wide range of diseases. While great progress has been achieved in the unveiling of the molecular mechanisms of programmed cell death, a new, and somehow puzzling level of complexity has recently begun to emerge, suggesting i) that several different self destruction pathways may exist and operate in parallel in our cells, and ii) that molecular effectors of cell suicide might also perform other functions unrelated to cell death induction and crucial to cell survival, such as cell differentiation, metabolism, and the regulation of the cell cycle. These new findings, with important physiopathological and therapeutic implications, seem at odds with the paradigm of programmed cell death derived from the studies of Caenorhabditis elegans, which led to the concept of the existence of selective, bona fide death genes that emerged and became selected for their sole capacity to execute or repress cell death. In this review, I will argue that this new level of complexity might only make sense and be understood when considered in a broader evolutionary context than that of our phylogenetic divergence from C. elegans. A new view of the regulated cell death pathways emerges when one attempts to ask the question of when and how they may have become selected during a timeline of 4 billion years, at the level of ancestral single-celled organisms, including the bacteria. I will argue that there may be no such thing as a bona fide genetic cell death program. Rather, in the framework of a model that I have termed the "original sin" hypothesis, I have proposed the existence of an initial pleiotropy of the molecular tools involved in the control and execution of self-destruction--an ancestral involvement in both pro-life and pro-death activities. I will discuss how this hypothesis may be reconciled with the C. elegans paradigm of programmed cell death. Finally I will discuss how an ancestral level of pleiotropic functions of the molecular tools involved in the control of cell death, aging and genetic diversification might have favored their initial selection, their constant availability for de novo selection, and their progressive propagation in most--if not all--species during the course of evolution.

Cell death was observed and understood since the 19th century, but there was no experimental examination until the mid-20th century. Beginning in the 1960's, several laboratories demonstrated that cell death was biologically controlled (programmed) and that the morphology was common and not readily explained (apoptosis). By 1990 the genetic basis of programmed cell death had been established and the first components of the cell death machinery (caspase 3, bcl-2 and Fas) had been identified, sequenced, and recognized as highly conserved in evolution. The rapid development of the field has given us substantial understanding of how cell death is achieved. However, capitalizing on our knowledge for therapeutic purposes requires us to learn much more about how a cell commits to death, as well as recognizing that apoptosis may be the most common and efficient means of death, but that there are alternative pathways that can result in cell death even when the conventional pathway is blocked. Interestingly enough, many of the arguments and missteps in the history of the field were anticipated by Claude Bernard, and his warnings and recommendations remain valid today.

Despite its relative anatomic simplicity, the nematode Caenorhabditis elegans (C. elegans) is a complex multicellular organism. In this review, we describe studies that have contributed to a better understanding of certain aspects of the worm's physiology. We focus on the cellular and molecular basis of the interaction between C. elegans and its environment, including its sensory capacities, the intrinsic biological clock that governs the speed of its life, and on some of the factors that control its life span. We also outline very recent findings that have demonstrated the existence of an innate immune system in C. elegans. Finally, we highlight a number of novel techniques that are transforming the worm from a largely genetic model system into an attractive organism for functional genomic studies.

The nematode C. elegans is an established model for developmental biology. Since the early 90's, this simple model organism has been increasingly used for studying human disease pathogenesis. C. elegans models based either on the mutagenesis of human disease genes conserved in this nematode or transgenesis with disease genes not conserved in C. elegans show several features that are observed in mammalian models. These observations suggest that the genetic dissection and pharmacological manipulation of disease-like phenotypes in C. elegans will shed light on the cellular mechanisms that are altered in human diseases, and the compounds that may be used as drugs. This review illustrates these aspects by commenting on two inherited degenerative diseases, Duchenne's muscular dystrophy and Huntington's neurodegenerative disease.

The human brain contains 100 billion neurons and probably one thousand times more synapses. Such a system can be analyzed at different complexity levels, from cognitive functions to molecular structure of ion channels. However, it remains extremely difficult to establish links between these different levels. An alternative strategy relies on the use of much simpler animals that can be easily manipulated. In 1974, S. Brenner introduced the nematode Caenorhabditis elegans as a model system. This worm has a simple nervous system that only contains 302 neurons and about 7,000 synapses. Forward genetic screens are powerful tools to identify genes required for specific neuron functions and behaviors. Moreover, studies of mutant phenotypes can identify the function of a protein in the nervous system. The data that have been obtained in C. elegans demonstrate a fascinating conservation of the molecular and cellular biology of the neuron between worms and mammals through more than 550 million years of evolution.

During early oogenesis, one cell from a cyst of 16 germ cells is selected to become the oocyte. Recent data suggest that the choice of this cell within the cyst is strongly biased as early as the cyst itself forms. However, it was further shown that, although selected, the oocyte fate needs to be maintained. The maintenance of the oocyte identity requires the activity of the Drosophila homologues of the Caenorhabditis elegans par genes. It was shown that the par genes are required for the first polarisation of the oocyte as early as in region 3 of the germarium. This reveals a striking conservation between the polarisation along the antero-posterior axis of the Caenorhabditis elegans one-cell embryo and the Drosophila oocyte.

The yeast genome has been completed and the almost 6000 proteins from the yeast proteome are under analysis. This analysis will contribute to elucidate the basic mechanisms of unicellular eucaryotic life. Several aspects of such studies are relevant to human health problems. In particular, it should allow the development of new fungicides which would be more efficient and specific and would escape the complex multidrug cell export systems developed by pathogenic fungi. Also several human genes determining hereditary diseases have yeast homologues. The function of these homologues can be determined using a series of genetic tools which are unique to yeast. These human genes can also be expressed in yeast and be submitted to the same tools. Several examples of these approaches will be chosen concerning yeast homologues of human membrane proteins belonging to ion channels, permeases, cation transport-ATPases or ABC transporters superfamilies.

The development of the nervous system implies not only the generation of neurons, but also their death. This neuronal death can occur through several mechanisms, one of them being apoptosis. This type of cell death seems to be also implicated in some neurodegenerative diseases. This study of the nematode Caenorhabditis elegans has led to the discovery of several genes controlling apoptosis in neurons. Two of them, the pro-apoptotic ced3 and the anti-apoptotic ced9, have mammalian homologs. The mammalian homologs to Ced9 form the Bcl-2 family and can be either pro-apoptotic or anti-apoptotic. Some of them, Bcl-x, and Bax have been shown to be involved in neuronal death during development in some pathological situations. The first mammalian homolog of Ced3 to be described was the Interleukin-1b Converting Enzymes (ICE). Since then, many other homologs of the proteases Ced3 and ICE have been discovered constituting the Caspases family. These Cysteinyl Aspartate Specific Proteases are pro-apoptotic in many different systems. Several studies using viral or peptidic inhibitors of the Caspases have demonstrated their role in neuronal death in vitro. In vivo, CPP32, a member of the Caspases family, has been shown to be clearly involved in the development of the nervous system. Finally, the analysis of apoptosis in Caenorhabditis elegans has led to the discovery of two families of genes involved in the cascade of events inducing neuronal death in mammals. Indeed, the Caspases seem to be controlled by the Bcl-2 family, as Ced3 is by Ced9.