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Elife,
2020]
As the demographics of the modern world skew older, understanding and mitigating the effects of aging is increasingly important within biomedical research. Recent studies in model organisms demonstrate that the aging process is frequently modified by an organism's ability to perceive and respond to changes in its environment. Many well-studied pathways that influence aging involve sensory cells, frequently neurons, that signal to peripheral tissues and promote survival during the presence of stress. Importantly, this activation of stress response pathways is often sufficient to improve health and longevity even in the absence of stress. Here, we review the current landscape of research highlighting the importance of cell non-autonomous signaling in modulating aging from <i>C. elegans</i> to mammals. We also discuss emerging concepts including retrograde signaling, approaches to mapping these networks, and development of potential therapeutics.
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[
Biotechniques,
1999]
We describe the use of modified versions of the Aequora victoria green fluorescent protein (GFP) to simultaneously follow the expression and distribution of two different proteins in the nematode, Caenorhabditis elegans. A cyan-colored GFP derivative, designated CFP, contains amino acid (aa) substitutions Y66W, N146I, M153T and V163A relative to the original GFP sequence and is similar to the previously reported "W7" form. A yellow-shifted GFP derivative, designated YFP, contains aa substitutions S65G, V68A, S72A and T203Y and is similar to the previously described "I0C" variant. Coding regions for CFP and YFP were constructed in the context of a high-activity C. elegans expression system. Previously characterized promoters and localization signals have been used to express CFP and YFP in C. elegans. Filter sets designed to distinguish YFP and CFP fluorescence spectra allowed visualization of the two distinct forms of GFP in neurons and in muscle cells. A series of expression vectors carrying CFP and YFP have been constructed and are being made available to the scientific community.
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J Neurosci,
2005]
The sensorimotor transformation underlying Caenorhabditis elegans chemotaxis has been difficult to measure directly under normal assay conditions. Thus, key features of this transformation remain obscure, such as its time course and dependence on stimulus amplitude. Here, we present a comprehensive characterization of the transformation as obtained by inducing stepwise temporal changes in attractant concentration within the substrate as the worm crawls across it. We found that the step response is complex, with multiple phases and a nonlinear dependence on the sign and amplitude of the stimulus. Nevertheless, the step response could be reduced to a simple kinetic model that predicted the results of chemotaxis assays. Analysis of the model showed that chemotaxis results from the combined effects of approach and avoidance responses to concentration increases and decreases, respectively. Surprisingly, ablation of the ASE chemosensory neurons, known to be necessary for chemotaxis in chemical gradient assays, eliminated avoidance responses but left approach responses intact. These results indicate that the transformation can be dissected into components to which identified neurons can be assigned.
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Aging Cell,
2017]
As in other poikilotherms, longevity in C.elegans varies inversely with temperature; worms are longer-lived at lower temperatures. While this observation may seem intuitive based on thermodynamics, the molecular and genetic basis for this phenomenon is not well understood. Several recent reports have argued that lifespan changes across temperatures are genetically controlled by temperature-specific gene regulation. Here, we provide data that both corroborate those studies and suggest that temperature-specific longevity is more the rule than the exception. By measuring the lifespans of worms with single modifications reported to be important for longevity at 15, 20, or 25C, we find that the effect of each modification on lifespan is highly dependent on temperature. Our results suggest that genetics play a major role in temperature-associated longevity and are consistent with the hypothesis that while aging in C. elegans is slowed by decreasing temperature, the major cause(s) of death may also be modified, leading to different genes and pathways becoming more or less important at different temperatures. These differential mechanisms of age-related death are not unlike what is observed in humans, where environmental conditions lead to development of different diseases of aging.
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[
Nat Commun,
2022]
An organism's ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity intervention, dietary restriction, acts in-part through a cell non-autonomous signaling pathway that is inhibited by the presence of attractive smells. Using an intestinal reporter for a key gene induced by dietary restriction but suppressed by attractive smells, we identify three compounds that block food odor effects in C. elegans, thereby increasing longevity as dietary restriction mimetics. These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food odor. We further identify a chemosensory neuron that likely perceives food odor, an enteric neuron that signals through the serotonin receptor 5-HT1A/SER-4, and a dopaminergic neuron that signals through the dopamine receptor DRD2/DOP-3. Aspects of this pathway are conserved in D. melanogaster. Thus, blocking food odor signaling through antagonism of serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction.
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Curr Top Membr,
2013]
A simple epithelium forms a barrier between the outside and the inside of an organism, and is the first organized multicellular tissue found in evolution. We examine the relationship between the evolution of epithelia and specialized cell-cell adhesion proteins comprising the classical cadherin/-catenin/-catenin complex (CCC). A review of the divergent functional properties of the CCC in metazoans and non-metazoans, and an updated phylogenetic coverage of the CCC using recent genomic data reveal: (1) The core CCC likely originated before the last common ancestor of unikonts and their closest bikont sister taxa. (2) Formation of the CCC may have constrained sequence evolution of the classical cadherin cytoplasmic domain and -catenin in metazoa. (3) The -catenin-binding domain in -catenin appears to be the favored mutation site for disrupting -catenin function in the CCC. (4) The ancestral function of the /-catenin heterodimer appears to be an actin-binding module. In some metazoan groups, more complex functions of -catenin were gained by sequence divergence in the non-actin-binding (N-, M-) domains. (5) Allosteric regulation of -catenin may have evolved for more complex regulation of the actin cytoskeleton.
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[
Curr Biol,
2004]
Defining the forces that sculpt genome organization is fundamental for understanding the origin, persistence, and diversification of species [1, 2]. The genomic sequences of the nematodes Caenorhabditis elegans and Caenorhabditis briggsae provide an excellent opportunity to explore the dynamics of chromosome evolution [3, 4]. Extensive chromosomal rearrangement has accompanied divergence from their common ancestor, an event occurring roughly 100 million years ago (Mya) [4]; yet, morphologically, these species are nearly indistinguishable and both reproduce primarily by self-fertilization. Here, we show that genes expressed during spermatogenesis (sperm genes) are nonrandomly distributed across the C. elegans genome into three large clusters located on two autosomes. In addition to sperm genes, these chromosomal regions are enriched for genes involved in the hermaphrodite sperm/oocyte switch and in the reception of sperm signals that control fertilization. Most loci are present in single copy, suggesting that cluster formation is largely due to gene aggregation and not to tandem duplication. Comparative mapping indicates that the C. briggsae genome differs dramatically from the C. elegans genome in clustering. Because clustered genes have a direct role in reproduction and thus fitness, their aggregated pattern might have been shaped by natural selection, perhaps as hermaphroditism evolved.
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[
Science,
2001]
Caenorhabditis elegans oocytes, like those of most animals, arrest during meiotic prophase. Sperm promote the resumption of meiosis (maturation) and contraction of smooth muscle-like gonadal sheath cells, which are required for ovulation. We show that the major sperm cytoskeletal protein (MSP) is a bipartite signal for oocyte maturation and sheath contraction. MSP also functions in sperm locomotion, playing a role analogous to actin. Thus, during evolution, MSP has acquired extracellular signaling and intracellular cytoskeletal functions for reproduction. Proteins with MSP-like domains are found in plants, fungi, and other animals, suggesting that related signaling functions may exist in other phyla.AD - Department of Cell Biology, Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.FAU - Miller, M AAU - Miller MAFAU - Nguyen, V QAU - Nguyen VQFAU - Lee, M HAU - Lee MHFAU - Kosinski, MAU - Kosinski MFAU - Schedl, TAU - Schedl TFAU - Caprioli, R MAU - Caprioli RMFAU - Greenstein, DAU - Greenstein DLA - engID - CA09592/CA/NCIID - GM57173/GM/NIGMSID - GM58008/GM/NIGMSID - HD07043/HD/NICHDID - HD25614/HD/NICHDPT - Journal ArticleCY - United StatesTA - ScienceJID - 0404511RN - 0 (Carrier Proteins)RN - 0 (Helminth Proteins)RN - 0 (MAP Kinase Signaling System)RN - 0 (Membrane Proteins)RN - 0 (Recombinant Proteins)RN - 0 (VAP-33 protein)RN - 0 (major sperm protein, nematode)RN - EC 2.7.1.- (Mitogen-Activated Protein Kinases)SB - IM
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[
Curr Biol,
2009]
At least 100 mammalian species exhibit embryonic diapause, where fertilized embryos arrest development in utero until suitable seasonal or nutritional environments are encountered. Delaying maternal investments in producing offspring allows these animals to utilize limited resources to survive while searching for better conditions and ensures that progeny are not produced when they are unlikely to survive. In addition, embryos may be protected from external environmental vicissitudes while in utero. Here we demonstrate embryonic diapause in C. elegans, and show that this diapause protects embryos from otherwise lethal hypoxia. Diapausing embryos in utero require
san-1 to survive, indicating that hypoxia-induced embryonic diapause may be mechanistically related to suspended animation. Furthermore, we show that neuronal HIF-1 activity in the adult dictates the O(2) tension at which embryonic diapause is engaged. We suggest that the maternal perception of hypoxia stimulates a response to protect embryos in utero by inducing diapause, a natural form of suspended animation. This response is likely to be an important strategy to improve offspring survival in harsh conditions and allow adults to find environments more suitable for reproductive success.
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CBE Life Sci Educ,
2009]
RNA interference (RNAi) is a powerful method to silence gene expression in a variety of organisms and is generating interest not only as a useful tool for research scientists but also as a novel class of therapeutics in clinical trials. Here, we report that undergraduate and graduate students with a basic molecular biology background were able to demonstrate conceptual knowledge and technical skills for using RNAi as a research tool upon completion of an intensive 8-wk RNAi course with a 2-h lecture and 5-h laboratory per week. Students were instructed on design of RNAi experiments in model organisms and perform multiweek laboratory sessions based on journal articles read and discussed in class. Using Nicotiana benthamiana, Caenorhabditis elegans, and mammalian cell culture, students analyzed the extent of silencing using both qualitative assessment of phenotypic variations and quantitative measurements of RNA levels or protein levels. We evaluated the course over two semesters, each with a separate instructor. In both semesters, we show students met expected learning outcomes as demonstrated by successful laboratory experiment results, as well as positive instructor assessments of exams and lab reports. Student self-assessments revealed increased confidence in conceptual knowledge and practical skills. Our data also suggest that the course is adaptable to different instructors with varying expertise.