Grimme, A. et al. (2019) International Worm Meeting "Elucidating the role of the miR-100 Family in C. elegans."

McJunkin, K., Grimme, A.

[International Worm Meeting, 2019]

MicroRNAs (miRNAs) are a class of small non-coding RNAs that are important post-transcriptional regulators of gene expression. A miRNA contains a "seed" sequence, typically located in nucleotides 2-7, that has complementarity to a region in a mRNA 3'UTR which allows for target recognition while the miRNA is loaded to the RNA-induced silencing complex (RISC). MiRNA families are comprised of microRNAs that share the same seed sequence, and due to the identical seed sequences, these family members can act redundantly while regulating targets. One of the most highly conserved miRNA families is the miR-100 family, which contains three family members in humans: miR-99a, miR-99b, and miR-100. These miRNAs are implicated in several medical conditions including cancer, obesity, heart disease, and others. In the model organism C. elegans, the miR-100 family microRNAs are known as the mir-51 family members, which includes six microRNAs: mir-51 through mir-56. Current knowledge of the essential functions of this family is relatively limited; one of the most important functions in C. elegans is its role in embryonic development. Given the highly conserved nature of the miR-100 family, understanding the vital functions of the mir-51 family may serve to elucidate how this family is involved in human diseases. While removing all mir-51 family members results in embryonic lethality, this project utilizes a hypomorphic strain with a slow growth phenotype to study the pathways regulated by this family. A portion of this project is dedicated to performing forward genetic screens to isolate suppressors of the slow growth phenotype. Reverse genetic screens using RNAi are performed alongside the forward screens to determine the roles of predicted mir-51 family targets in the slow growth phenotype. Preliminary data from these screens suggest that the slow growth phenotype can be alleviated through isolated suppressors as well as through performing RNAi against certain mir-51 family targets. In the future these results may help to elucidate specific functions of the mir-51 family in C. elegans, which may represent conserved functions of the miR-100 family that can be studied further to determine the connection between this family and human diseases.

Grimm, Julie E et al. (2013) International Worm Meeting "How to Fix a Broken Neuron."

Podbilewicz, Benjamin, Grimm, Julie E, Oren, Meital

[International Worm Meeting, 2013]

Recent research in C. elegans, Drosophila and mice has aimed at investigating the regenerative ability of neurons. In contrast to previous understanding, studies of dendritic and axonal injury revealed hugely dynamic and moderately successful recovery. Our work seeks to elucidate the elements necessary for dendritic recovery to injury in order to expand our limited view of neuronal plasticity, maintenance and stability. Our model neuron, the mechanosensory PVD, is the most arborized neuron in C. elegans. The PVD response to dendritic injury follows a certain pattern: bypass of self-avoidance mechanisms followed by reattachment at or near the site of injury, sprouting and simplification of branches. Failure of PVD reattachment results in degeneration of the distal fragment. Our work focuses on the arborization functions of NHR-25 (a nuclear hormone receptor) and EFF-1 (epidermal fusion failure 1, a cell-cell fusion protein) and their roles in dendritic fusion. The nuclear hormone receptor NHR-25 is known to be essential for epidermal and vulva development in C. elegans. We found that NHR-25 is also important for normal arborization, maintenance of dendritic trees and injury response. nhr-25 deficient worms show excess branching at and around the site of injury up to 50 hours post injury, a time when ectopic branching in response to injury would normally be pruned back. Through epistatic analysis we discovered that this function is consistent with a model in which nhr-25 positively regulates eff-1. By analyzing NHR-25 expression dynamics using an NHR-25::GFP translational reporter we found that NHR-25 expression is reduced in the hypodermis in response to injury . These results suggest that nhr-25 regulates PVD branching and branch fusion non-cell autonomously. We are performing tissue-specific rescue of the nhr-25 arborization phenotypes to determine whether nhr-25 functions in PVD repair from the hypodermis. We have previously shown that EFF-1 acts cell autonomously in the PVD, suggesting that eff-1 and nhr-25 may act in parallel pathways. Our finding provides a link between the external and internal neuronal environment and the regenerative ability of the neuron itself.

Quartey MO et al. (2021) Sci Rep "The A(1-38) peptide is a negative regulator of the A(1-42) peptide implicated in Alzheimer disease progression."

Pennington PR, Heistad RM, Nyarko JNK, Barnes JR, Bolanos MAC, Parsons MP, Knudsen KJ, De Carvalho CE, Leary SC, Mousseau DD, Buttigieg J, Maley JM, Quartey MO

[Sci Rep, 2021]

The pool of -Amyloid (A) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A peptides. We examined how a naturally occurring variant, e.g. A(1-38), interacts with the AD-related variant, A(1-42), and the predominant physiological variant, A(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A(1-38) interacts differently with A(1-40) and A(1-42) and, in general, A(1-38) interferes with the conversion of A(1-42) to a -sheet-rich aggregate. Functionally, A(1-38) reverses the negative impact of A(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A(1-42) phenotype in Caenorhabditis elegans. A(1-38) also reverses any loss of MTT conversion induced by A(1-40) and A(1-42) in HT-22 hippocampal neurons and APOE 4-positive human fibroblasts, although the combination of A(1-38) and A(1-42) inhibits MTT conversion in APOE 4-negative fibroblasts. A greater ratio of soluble A(1-42)/A(1-38) [and A(1-42)/A(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A(1-42).

Danielle Thierry-Mieg et al. (2003) Worm Breeder's Gazette "www.wormgenes.org , a new gene centered database"

Vahan Simonyan, Michel Potdevin, Mark Sienkiewicz, Yuji KOHARA, Jean Thierry-Mieg, Danielle Thierry-Mieg, Tadasu SHIN-I

[Worm Breeder's Gazette, 2003]

Wormgenes is a new resource for C.elegans offering a detailed summary about each gene and a powerful query system.

Tangrodchanapong T et al. (2020) Front Pharmacol "Frondoside A Attenuates Amyloid- Proteotoxicity in Transgenic Caenorhabditis elegans by Suppressing Its Formation."

Tangrodchanapong T, Sobhon P, Meemon K

[Front Pharmacol, 2020]

Oligomeric assembly of Amyloid- (A) is the main toxic species that contribute to early cognitive impairment in Alzheimer's patients. Therefore, drugs that reduce the formation of A oligomers could halt the disease progression. In this study, by using transgenic <i>Caenorhabditis elegans</i> model of Alzheimer's disease, we investigated the effects of frondoside A, a well-known sea cucumber <i>Cucumaria frondosa</i> saponin with anti-cancer activity, on A aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 M significantly delayed the worm paralysis caused by A aggregation as compared with control group. In addition, the number of A plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of A species in the transgenic <i>C. elegans</i> were significantly reduced upon treatment with frondoside A, whereas the level of A monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of A. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express A. Taken together, these data suggested that low dose of frondoside A could protect against A-induced toxicity by primarily suppressing the formation of A oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-A aggregation should be studied and elucidated in the future.

Hodgkin JA (1998) International Journal of Developmental Biology "Seven types of pleiotropy."

Hodgkin JA

[International Journal of Developmental Biology, 1998]

Pleiotropy , a situation in which a single gene influences multiple phenotypic tra its, can arise in a variety of ways. This paper discusses possible underlying mechanisms and proposes a classification of the various phenomena involved.

Tuck S (2011) Curr Biol "Extracellular vesicles: budding regulated by a phosphatidylethanolamine translocase."

Tuck S

[Curr Biol, 2011]

Recent work on a Caenorhabditis elegans transmembrane ATPase reveals a central role for the aminophospholipid phosphatidylethanolamine in the production of a class of extracellular vesicles.

Viney ME et al. (2004) Naturwissenschaften "Is dauer pheromone of Caenorhabditis elegans really a pheromone?"

Viney ME, Franks NR

[Naturwissenschaften, 2004]

Animals respond to signals and cues in their environment. The difference between a signal (e.g. a pheromone) and a cue (e.g. a waste product) is that the information content of a signal is subject to natural selection, whereas that of a cue is not. The model free-living nematode Caenorhabditis elegans forms an alternative developmental morph (the dauer larva) in response to a so-called 'dauer pheromone', produced by all worms. We suggest that the production of 'dauer pheromone' has no fitness advantage for an individual worm and therefore we propose that 'dauer pheromone' is not a signal, but a cue. Thus, it should not be called a pheromone.

Schaeffer JM et al. (1990) J Antibiot (Tokyo) "Cochlioquinone A, a nematocidal agent which competes for specific [3H]ivermectin binding sites."

Williamson JM, Schaeffer JM, Bergstrom AR, Liesch JM, Goetz MA, Frazier EG

[J Antibiot (Tokyo), 1990]

Cochlioquinone A, isolated from the fungus Helminthosporium sativum, was found to have nematocidal activity. Cochlioquinone A is a competitive inhibitor of specific [3H]ivermectin binding suggesting that cochlioquinone A and ivermectin interact with the same membrane receptor.

Desta IT et al. (2016) J Lab Autom "Detecting and Trapping of a Single C. elegans Worm in a Microfluidic Chip for Automated Microplate Dispensing."

Giakoumidis N, Mustafa N, AlGharibeh N, Orozaliev A, Al-Sharif A, Song YA, Desta IT, Gunsalus KC

[J Lab Autom, 2016]

Microfluidic devices offer new technical possibilities for a precise manipulation of Caenorhabditis elegans due to the comparable length scale. C. elegans is a small, free-living nematode worm that is a popular model system for genetic, genomic, and high-throughput experimental studies of animal development and neurobiology. In this paper, we demonstrate a microfluidic system in polydimethylsiloxane (PDMS) for dispensing of a single C. elegans worm into a 96-well plate. It consists of two PDMS layers, a flow and a control layer. Using five microfluidic pneumatic valves in the control layer, a single worm is trapped upon optical detection with a pair of optical fibers integrated perpendicular to the constriction channel and then dispensed into a microplate well with a dispensing tip attached to a robotic handling system. Due to its simple design and facile fabrication, we expect that our microfluidic chip can be expanded to a multiplexed dispensation system of C. elegans worms for high-throughput drug screening.