McLaughlin CN et al. (2018) Trends Genet "Keeping Neurons Young and Foxy: FoxOs Promote Neuronal Plasticity."

McLaughlin CN, Broihier HT

[Trends Genet, 2018]

Any adult who has tried to take up the piano or learn a new language is faced with the sobering realization that acquiring such skills is more challenging as an adult than as a child. Neuronal plasticity, or the malleability of brain circuits, declines with age. Young neurons tend to be more adaptable and can alter the size and strength of their connections more readily than can old neurons. Myriad circuit- and synapse-level mechanisms that shape plasticity have been identified. Yet, molecular mechanisms setting the overall competence of young neurons for distinct forms of plasticity remain largely obscure. Recent studies indicate evolutionarily conserved roles for FoxO proteins in establishing the capacity for cell-fate, morphological, and synaptic plasticity in neurons.

Beale EG (2008) Exp Biol Med (Maywood) "5'-AMP-activated protein kinase signaling in Caenorhabditis elegans."

Beale EG

[Exp Biol Med (Maywood), 2008]

5''-AMP-activated protein kinase (AMPK) has been called "the metabolic master switch" because of its central role in regulating fuel homeostasis. AMPK, a heterotrimeric serine/threonine protein kinase composed of alpha, beta, and gamma subunits, is activated by upstream kinases and by 5''-AMP in response to various nutritional and stress signals. Downstream effects include regulation of metabolism, protein synthesis, cell growth, and mediation of the actions of a number of hormones, including leptin. However, AMPK research represents a young and growing field; hence, there are many unanswered questions regarding the control and action of AMPK. This review presents evidence for the existence of AMPK signaling pathways in Caenorhabditis elegans, a genetically tractable model organism that has yet to be fully exploited to elucidate AMPK signaling mechanisms.

Frezal L et al. (2015) Elife "C. elegans outside the Petri dish."

Frezal L, Felix MA

[Elife, 2015]

The roundworm Caenorhabditis elegans has risen to the status of a top model organism for biological research in the last fifty years. Among laboratory animals, this tiny nematode is one of the simplest and easiest organisms to handle. And its life outside the laboratory is beginning to be unveiled. Like other model organisms, C. elegans has a boom-and-bust lifestyle. It feasts on ephemeral bacterial blooms in decomposing fruits and stems. After resource depletion, its young larvae enter a migratory diapause stage, called the dauer. Organisms known to be associated with C. elegans include migration vectors (such as snails, slugs and isopods) and pathogens (such as microsporidia, fungi, bacteria and viruses). By deepening our understanding of the natural history of C. elegans, we establish a broader context and improved tools for studying its biology.

Rothstein M (1980) "Effects of aging on enzymes."

Rothstein M

[1980]

The practical use of free-living nematodes for aging studies must overcome two problems. Not only must cultures begin with organisms of a similar age, but also reproduction must be prevented, or synchrony will be lost and the aging cultures will become contaminated with newborn orrganisms and will eventually revert to typical "mixed" cultures. The problem of obtaining uniformly small organisms to start cultures has been solved by the use of screens for Turbatrix aceti and the hatching of isolated egg masses for Caenorhabditis elegans. Subsequent reproduction is prevented by the use of the DNA inhibitor fluorodeoxyuridine, or by culturing the organisms at elevated temperatures. Another practical method for aging of T. aceti is the use of a repeated screening process that periodically removes small (young) organisms from the aging cultures.

Golden TR et al. (2006) Exp Gerontol "Microarray analysis of variation in individual aging C. elegans: approaches and challenges."

Golden TR, Melov S, Hubbard A

[Exp Gerontol, 2006]

Aging is generally defined and studied as a population phenomenon. However, there is great interest, especially when discussing human aging, in the identification of factors that influence the life span of an individual organism. The nematode Caenorhabditis elegans provides an excellent model system for the study of aging at the level of the individual, since young nematodes are essentially clonal yet experience a large range of individual life spans. We are conducting gene expression profiling of individual nematodes, with the aim of discovering genes that vary stochastically in expression between individuals of the same age. Such genes are candidates to modulate the ultimate life span achieved by each individual. We here present statistical analysis of gene expression profiles of individual nematodes from two different microarray platforms, examining the issue of technical vs. biological variance as it pertains to uncovering genes of interest in this paradigm of individual aging.

Silva MH (2020) Birth Defects Res "Effects of low-dose chlorpyrifos on neurobehavior and potential mechanisms: A review of studies in rodents, zebrafish, and Caenorhabditis elegans."

Silva MH

[Birth Defects Res, 2020]

OBJECTIVES: Exposure to chlorpyrifos (CPF), a neurotoxic insecticide, is implicated with adverse neurodevelopmental effects in children through noncholinergic mechanisms. METHODS: This review presents qualitative and quantitative evidence in three animal models (rodent, zebrafish, and Caenorhabditis elegans), for neurodevelopmental and behavioral effects occurring at CPF doses lower than those inhibiting acetylcholinesterase (AChE). RESULTS: ). Zebrafish had cognitive and anxiety deficits after CPF treatment at low doses and young adult C. elegans had reproductive dysfunction associated NMF and disruption of the serotonergic pathway. Quantitative data for all three species showed neurobehavioral effects after exposure to CPF doses approximately 2-10-fold below the threshold for AChE inhibition. CONCLUSIONS: Taken together, these findings provided a weight-of-evidence for low-dose CPF neurotoxicity and noncholinergic mechanisms. Variability in laboratories, exposure methods, tests, sex, and animal species/strain might have contributed to the inconsistent results. The detrimental CPF effects during early development are relevant to human populations.

Hopkins CE et al. (2022) Mol Aspects Med "Phenotypic screening models for rapid diagnosis of genetic variants and discovery of personalized therapeutics."

Brock T, Bainbridge M, Caulfield TR, Hopkins CE

[Mol Aspects Med, 2022]

Precision medicine strives for highly individualized treatments for disease under the notion that each individual's unique genetic makeup and environmental exposures imprints upon them not only a disposition to illness, but also an optimal therapeutic approach. In the realm of rare disorders, genetic predisposition is often the predominant mechanism driving disease presentation. For such, mostly, monogenic disorders, a causal gene to phenotype association is likely. As a result, it becomes important to query the patient's genome for the presence of pathogenic variations that are likely to cause the disease. Determining whether a variant is pathogenic or not is critical to these analyses and can be challenging, as many disease-causing variants are novel and, ergo, have no available functional data to help categorize them. This problem is exacerbated by the need for rapid evaluation of pathogenicity, since many genetic diseases present in young children who will experience increased morbidity and mortality without rapid diagnosis and therapeutics. Here, we discuss the utility of animal models, with a focus mainly on C. elegans, as a contrast to tissue culture and in silico approaches, with emphasis on how these systems are used in determining pathogenicity of variants with uncertain significance and then used to screen for novel therapeutics.

Tatar M et al. (2001) Experimental Gerontology "Slow aging during insect reproductive diapause: why butterflies, grasshoppers and flies are like worms"

Yin C, Tatar M

[Experimental Gerontology, 2001]

Diapause is a state of arrested development accompanied by physiology for somatic persistence. Diapause is common in many invertebrates and is familiar to biogerontology in the context of Caenorhabditis elegans dauer. Among insects, diapause may occur in embryos, larvae, pupae or adults. At the adult stage, reproductive diapause arrests development of oogenesis, vitellogenesis, accessory gland activity, and mating behavior. Reproductive diapause has been well studied in monarch butterflies, several grasshoppers, and several Diptera, including Drosophila and Phormia. In monarchs and in grasshoppers, reproductive diapause physiology has been experimentally induced by the surgical removal of the corpora allata, the source of adult juvenile hormone; allatectomy in each case was found to double adult longevity. Among Drosophila, the endemic D. triauraria of Japan, and D. littoralis of Finland over-winter as adults in reproductive diapause. How D. melanogaster winter is poorly understood, but reproductive diapause can be cued by cool temperature. In laboratory studies, the mortality rates of post-diapause D. melanogaster are similar to rates of newly enclosed, young flies. This implies that senescence during diapause is slow or negligible. Slow aging during the diapause period may involve elevated somatic stress resistance as well as reallocation of resources to somatic maintenance. Reproductive diapause in Drosophila is proximally controlled by down regulation of juvenile hormone, a phenotype that is also produced by mutants of the insulin-like receptor InR, homologue of C. elegans daf-2. We propose neuroendocrine control of reproductive diapause in D. melanogaster that includes phenotypic plasticity for rates of senescence.

Smith JJ et al. (2022) Semin Cell Dev Biol "Hox gene functions in the C. elegans nervous system: From early patterning to maintenance of neuronal identity."

Smith JJ, Kratsios P

[Semin Cell Dev Biol, 2022]

The nervous system emerges from a series of genetic programs that generate a remarkable array of neuronal cell types. Each cell type must acquire a distinct anatomical position, morphology, and function, enabling the generation of specialized circuits that drive animal behavior. How are these diverse cell types and circuits patterned along the anterior-posterior (A-P) axis of the animal body? Hox genes encode transcription factors that regulate cell fate and patterning events along the A-P axis of the nervous system. While most of our understanding of Hox-mediated control of neuronal development stems from studies in segmented animals like flies, mice, and zebrafish, important new themes are emerging from work in a non-segmented animal: the nematode Caenorhabditis elegans. Studies in C. elegans support the idea that Hox genes are needed continuously and across different life stages in the nervous system; they are not only required in dividing progenitor cells, but also in post-mitotic neurons during development and adult life. In C. elegans embryos and young larvae, Hox genes control progenitor cell specification, cell survival, and neuronal migration, consistent with their neural patterning roles in other animals. In late larvae and adults, C. elegans Hox genes control neuron type-specific identity features critical for neuronal function, thereby extending the Hox functional repertoire beyond early patterning. Here, we provide a comprehensive review of Hox studies in the C. elegans nervous system. To relate to readers outside the C. elegans community, we highlight conserved roles of Hox genes in patterning the nervous system of invertebrate and vertebrate animals. We end by calling attention to new functions in adult post-mitotic neurons for these paradigmatic regulators of cell fate.

Bertucci A et al. (2009) J Radiat Res (Tokyo) "Microbeam irradiation of the C. elegans nematode."

Randers-Pehrson G, Brenner DJ, Pocock RD, Bertucci A

[J Radiat Res (Tokyo), 2009]

The understanding of complex radiation responses in biological systems, such as non-targeted effects as represented by the bystander response, can be enhanced by the use of genetically amenable model organisms. Almost all bystander studies to date have been carried out by using conventional single-cell in vitro systems, which are useful tools to characterize basic cellular and molecular responses. A few studies have been reported in monolayer explants and bystander responses have been also investigated in a three-dimensional normal human tissue system. However, despite the well-know usefulness of in vitro models, they cannot capture the complexity of radiation responses of living systems such as animal models. To carry out in vivo studies on the bystander effect we have developed a new technique to expose living organisms using proton microbeams. We report the use of a nematode C. elegans strain with a Green Fluorescent Protein (GFP) reporter for the hsp-4 heat-shock gene as an in vivo model for radiation studies. Exposing animals to heat and chemicals stressors leads to whole body increases in the hsp-4 protein reflected by enhanced fluorescence. We report here that gamma-rays also can induce stress response in a dose dependent manner. However, whole body exposure to stress agents does not allow for evaluation of distance dependent response in non targeted tissues: the so-called bystander effect. We used the RARAF microbeam to site specifically deliver 3 MeV protons to a site in the tail of young worms. GFP expression was enhanced after 24 hours in a number dependent manner at distances > 100 microm from the site of irradiation.