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Lipids Health Dis,
2016]
Fundamental questions remain unresolved in diabetes: What is the actual mechanism of glucose toxicity? Why is there insulin resistance in type 2 diabetes? Why do diets rich in sugars or saturated fatty acids increase the risk of developing diabetes? Studying the C. elegans homologs of the anti-diabetic adiponectin receptors (AdipoR1 and AdipoR2) has led us to exciting new discoveries and to revisit what may be termed "The Membrane Theory of Diabetes". We hypothesize that excess saturated fatty acids (obtained through a diet rich in saturated fats or through conversion of sugars into saturated fats via lipogenesis) leads to rigid cellular membranes that in turn impair insulin signalling, glucose uptake and blood circulation, thus creating a vicious cycle that contributes to the development of overt type 2 diabetes. This hypothesis is supported by our own studies in C. elegans and by a wealth of literature concerning membrane composition in diabetics. The purpose of this review is to survey this literature in the light of the new results, and to provide an admittedly membrane-centric view of diabetes.
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J Biol,
2008]
ABSTRACT: Systematic mapping of genetic-interaction networks will provide an essential foundation for understanding complex genetic disorders, mechanisms of genetic buffering and principles of robustness and evolvability. A recent study of signaling pathways in Caenorhabditis elegans lays the next row of bricks in this foundation.
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Organogenesis,
2012]
The extracellular matrix (ECM) plays an essential role in organizing tissues, defining their shapes or in presenting growth factors. Their components have been well described in most species, but our understanding of the mechanisms that control ECM remodeling remains limited. Likewise, how the ECM contributes to cellular mechanical responses has been examined in few cases. Here, I review how studies performed in C. elegans have brought several significant advances on those topics. Focusing only on epithelial cells, I discuss basement membrane invasion by the anchor cell during vulva morphogenesis, a process that has greatly expanded our knowledge of ECM remodeling in vivo. I then discuss the ECM role in a novel mechanotransduction process, whereby muscle contractions stimulate the remodeling of hemidesmosome-like junctions in the epidermis, which highlights that these junctions are mechanosensitive. Finally, I discuss progress in defining the composition and potential roles of the apical ECM covering epidermal cells in embryos.
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Development,
1990]
Embryonic processes in the nematode C. elegans, the gastropod mollusc Ilyanassa, the dipteran Drosophila, the echinoid Strongylocentrotus purpuratus, the ascidian Ciona, the anuran Xenopus, the teleost Brachydanio and mouse are compared with respect to a series of parameters such as invariant or variable cleavage, the means by which the embryonic axes are set up, egg anisotropies and reliance on conditional or on autonomous specification processes. A molecular interpretation of these modes of specification of cell fate in the embryo is proposed, in terms of spatial modifications of gene regulatory factors. On this basis, classically defined phenomena such as regulative development and cytoplasmic localization can be interpreted at a mechanistic level, and the enormous differences between different forms of embryogenesis in the Animal Kingdom can be considered within a common mechanistic framework. Differential spatial expression of histospecific genes is considered in terms of the structure of the gene regulatory network that will be required in embryos that utilize cell-cell interaction, autonomous vs conditional specification and maternal spatial information to differing extents. It is concluded that the regulatory architectures according to which the programs of gene expression are organized are special to each form of development, and that common regulatory principles are to be found only at lower levels, such as those at which the control regions of histospecific structural genes operate.
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Mol Neurobiol,
2008]
Inclusion body myositis (IBM) is the most common myopathy in people over 50 years of age. It involves an inflammatory process that, paradoxically, does not respond to anti-inflammatory drugs. A key feature of IBM is the presence of amyloid-beta-peptide aggregates called amyloid deposits, which are also characteristic of Alzheimer''s disease. The use of animals that mimic at least some characteristics of a disease has become very important in the quest to elucidate the molecular mechanisms underlying this and other pathogeneses. Although there are some transgenic mouse strains that recreate some aspects of IBM, in this review, we hypothesize that the great degree of similarity between nematode and human genes known to be involved in IBM as well as the considerable conservation of biological mechanisms across species is an important feature that must be taken into consideration when deciding on the use of this nematode as a model. Straightforward laboratory techniques (culture, transformation, gene knockdown, genetic screenings, etc.) as well as anatomical, physiological, and behavioral characteristics add to the value of this model. In the present work, we review evidence that supports the use of Caenorhabditis elegans as a biological model for IBM.
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Cell Death Differ,
2018]
The last 30 years of studying BCL2 have brought cell death research into the molecular era, and revealed its relevance to human pathophysiology. Most, if not all metazoans use an evolutionarily conserved process for cellular self destruction that is controlled and implemented by proteins related to BCL2. We propose the anti-apoptotic BCL2-like and pro-apoptotic BH3-only members of the family arose through duplication and modification of genes for the pro-apoptotic multi-BH domain family members, such as BAX and BAK1. In that way, a cell suicide process that initially evolved as a mechanism for defense against intracellular parasites was then also used in multicellular organisms for morphogenesis and to maintain the correct number of cells in adults by balancing cell production by mitosis.
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Int Angiol,
2005]
The mechanism of initiation and growth of a thrombus in atherosclerotic arteries, although investigated extensively, has not been sufficiently elucidated. Understanding the molecular mechanisms that lead to stroke, unstable angina and myocardial infarction is of paramount importance. Protease-activated receptors (PARs) belong to a recently discovered and so far not fully characterized family of transmembrane proteins, which are involved in the initiation growth of thrombi in atherosclerotic arteries. PARs are a G-protein-coupled family of receptors which mediate a cellular function with the aid of enzymes. All of them have identical structural organization and are activated by a very similar mechanism. The enzyme (serine protease) cleaves an extracellular amino-terminal fragment of the receptor in order to unmask a new amino-terminal, 5-6 residues of which serve as the tethering ligand, able to activate its maternal receptor. According to the most recently published reports, in eukaryotic organisms there are 5 different PARs: from PAR 1 to PAR 4 found in human organisms and PAR 5 discovered as a 14-3-3 protein, identified firstly in C. elegans and Drosophila melanogaster. Up to now numerous experiments have been conducted with the aim to understand more precisely the mechanisms of PARs activation and activity. The present paper summarizes the most important and most recently published reports concerning this problem, which seems to be most relevant in angiology.
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Dev Dyn,
2010]
The Netrin family of extracellular ligands and their receptors were the first identified signaling pathway regulating axon guidance. Subsequent work across model systems has begun to reveal the interactions that take place downstream of Netrin reception to facilitate growth cone migration. Though intensely studied, many aspects of this signaling system remain unclear. Even less understood are the growing number of contexts in which Netrin signaling influences cells beyond axon guidance and even outside the nervous system. Genetic and cell-biological studies in C. elegans have played an instrumental role in identifying critical functions for Netrin ligands in setting up specialized and potentially adhesive membrane-associated domains within a broad range of cell types. Here we review recent literature implicating Netrin or its receptors in morphogenetic processes outside of growth cone regulation with a special focus on studies in C. elegans that suggest cell biological mechanisms for Netrin signaling.
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Curr Opin Neurobiol,
2012]
The unique ability of chemical synapses to transmit information relies on the structural organization of presynaptic terminals. Empowered by forward genetics, research using Caenorhabditis elegans has continued to make pivotal contributions to discover conserved regulators and pathways for presynaptic development. Recent advances in microscopy have begun to pave the path for linking molecular dynamics with subsynaptic structures. Studies using diverse reporters for synapses further broaden the landscape of regulatory mechanisms underlying presynaptic differentiation. The identification of novel regulators at transcriptional and post-transcriptional levels raises new questions for understanding synapse formation at the genomic scale.
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Bioessays,
2020]
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.