Chen X et al. (2015) Mol Neurodegener "Erratum to: Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression."

McCue HV, Chen X, Morgan A, Kashyap SS, Barclay JW, Kraemer BC, Burgoyne RD, Wong SQ

[Mol Neurodegener, 2015]

The original version of this article [1] unfortunately contained a mistake. The author list contained a spelling error for the author Hannah V. McCue. The original article has been corrected for this error. The corrected author list is given below:Xi Chen, Hannah V. McCue, Shi Quan Wong, Sudhanva S. Kashyap, Brian C. Kraemer, Jeff W. Barclay, Robert D. Burgoyne and Alan Morgan

Sternberg PW (1990) Adv Genet "Genetic control of cell type and pattern formation in Caenorhabditis elegans."

Sternberg PW

[Adv Genet, 1990]

As recognized by T. H. Morgan, the problems of genetics and development are interwoven. Morgan noted that understanding how the genotype of an organism specifies its phenotype would require knowing the fundamental mechanisms of gene action, how genes interact to specify the properties of cells, and how cells interact to specify each adult character. We now have a basic understanding of the primary effects of genes (to encode protein or RNA products). However, little is known about how the genes of a zygote specify a complex pattern of cell divisions, the generation of diverse cell types, and the arrangement of those cells into specific morphological structures. A "favorable material" (as Morgan put it) for investigating these problems would be a simple organism in which development could be analyzed at the level of single genes and single cells. The small free-living soil nematode Caenorhabditis elegans is such an organism...

Haloupek N (2019) Genetics "Barbara J. Meyer: 2018 Thomas Hunt Morgan Medal."

Haloupek N

[Genetics, 2019]

The Genetics Society of America's (GSA) Thomas Hunt Morgan Medal honors researchers for lifetime achievement in genetics. The recipient of the 2018 Morgan Medal, Barbara J. Meyer of the Howard Hughes Medical Institute and the University of California, Berkeley, is recognized for her career-long, groundbreaking investigations of how chromosome behaviors are controlled. Meyer's work has revealed mechanisms of sex determination and dosage compensation in <i>Caenorhabditis elegans</i> that continue to serve as the foundation of diverse areas of study on chromosome structure and function today, nearly 40 years after she began her work on the topic.

Hwang HY et al. (2017) PLoS Comput Biol "Effect of mutation mechanisms on variant composition and distribution in Caenorhabditis elegans."

Wang J, Hwang HY

[PLoS Comput Biol, 2017]

Genetic diversity is maintained by continuing generation and removal of variants. While examining over 800,000 DNA variants in wild isolates of Caenorhabditis elegans, we made a discovery that the proportions of variant types are not constant across the C. elegans genome. The variant proportion is defined as the fraction of a specific variant type (e.g. single nucleotide polymorphism (SNP) or indel) within a broader set of variants (e.g. all variants or all non-SNPs). The proportions of most variant types show a correlation with the recombination rate. These correlations can be explained as a result of a concerted action of two mutation mechanisms, which we named Morgan and Sanger mechanisms. The two proposed mechanisms act according to the distinct components of recombination rate, specifically the genetic and physical distance. Regression analysis was used to explore the characteristics and contributions of the two mutation mechanisms. According to our model, ~20-40% of all mutations in C. elegans wild populations are derived from programmed meiotic double strand breaks, which precede chromosomal crossovers and thus may be the point of origin for the Morgan mechanism. A substantial part of the known correlation between the recombination rate and variant distribution appears to be caused by the mutations generated by the Morgan mechanism. Mathematically integrating the mutation model with background selection model gives a more complete depiction of how the variant landscape is shaped in C. elegans. Similar analysis should be possible in other species by examining the correlation between the recombination rate and variant landscape within the context of our mutation model.

Gerhold AR et al. (2016) Dev Cell "Bigger Isn't Always Better: Cell Size and the Spindle Assembly Checkpoint."

Maddox PS, Gerhold AR, Labbe JC

[Dev Cell, 2016]

Variation in the activity of the spindle assembly checkpoint has been observed in different cell types, yet the reason for this variability remains poorly understood. Reporting in Developmental Cell, Galli and Morgan (2016) show that checkpoint activity increases during development as cell size, and the cytoplasm-to-kinetochore ratio, decreases.

Voegtlin, Thomas et al. (2011) International Worm Meeting "An Open-Source Neuromechanical Model of C. Elegans Locomotion."

Cohen, Netta, Voegtlin, Thomas

[International Worm Meeting, 2011]

A neuromechanical model of locomotion in C. elegans was recently proposed by Jordan H. Boyle [1]. One of the main results is that both swimming and crawling can be generated by a single neural circuit, reflexively modulated by the environment. This supports the known experimental results showing that different forms of C. elegans forward locomotion (e.g., swimming and crawling) can be described by a modulation of a single biomechanical gait [2]. The modelling result illustrates the importance and the potential of neuromechanical simulations for the analysis of the worm's behaviour. In order to continue this work, and to make it usable by a broader audience, we have developed a similar neuromechanical model of the worm using CLONES. CLONES (Closed Loop Neural Simulation) is an open source framework for neuromechanical simulations. CLONES implements a communication interface between a neural simulator, called BRIAN [3], and a physics engine for biomedical applications, called SOFA [4]. BRIAN and SOFA are open-source simulators that are easy to use and provide high performance. Our implementation of the worm's locomotion reproduces the neural model described in [1]. However, there are two key differences between the original physical model and our implementation. Firstly, Boyle's model considers that the body of the worm has zero mass (a low Reynolds number approximation). In contrast, the SOFA simulator allows us to integrate equations with mass and inertia. Secondly, the original model uses rigid rods of fixed length orthogonal to the body axis (approximating the incompressibility of the body due to high internal pressure). In SOFA rigid rods are modeled as springs of very high stiffness. The physical system simulated in SOFA is described using a XML syntax. The neural network model interpreted by BRIAN is written in Python, using MATLAB-like syntax. Thus, the model is completely interpreted, and it is possible to visualize/interact with the simulation during runtime. Physical environments containing obstacles or chemical concentration gradients can be defined easily. References 1. Boyle JH: C. elegans locomotion: an integrated approach. PhD thesis, university of Leeds, 2009 2. Berri S, Boyle JH, Tassieri M, Hope IA and Cohen N, Forward locomotion of the nematode C. elegans is achieved through modulation of a single gait HFSP J 3:186, 2009; 3. Goodman DF, Brette R: Brian: a simulator for spiking neural networks in Python. Front Neuroinform 2:5, 2008 4. Allard J, Cotin S, Faure F, Bensoussan PJ, Poyer F, Duriez C, Delingette H, Grisoni L: SOFA - an Open Source Framework for Medical Simulation. Medicine Meets Virtual Reality (MMVR'15), pp. 13-18, 2007.

Duke BO (1990) Parasitol Today "Onchocerciasis (river blindness)- can it be eradicated?"

Duke BO

[Parasitol Today, 1990]

Onchocerca volvulus causes a disease of significant socio-economic importance in West Africa, the Arabian Peninsula and regions of South America. Brian Duke explains that, despite the advent of ivermectin, the prospects for the eradication of this potentially highly debilitating infection are remote. Moreover, the logistical problems associated with the control of morbidity caused by the parasite are considerable, and are highly dependent on the ability to sustain financial support and political will over many decades.

K Lundin et al. (1999) International C. elegans Meeting "Ethanol Tolerance in C. elegans"

K Lundin, PC Phillips

[International C. elegans Meeting, 1999]

It is thought that increased ethanol tolerance in humans leads to increased risk of alcoholism. Unfortunately, not much is known about the genetics and physiology of ethanol tolerance, and therefore we have begun a set of preliminary experiments on this topic using Caenorhabditis elegans as a model system. Individuals were tested for initial tolerance over a wide range of ethanol concentrations, yielding a determination of the lethal concentration. Initial tolerance to ethanol after five minutes of exposure was surprisingly high, with a tolerance threshold of approximately 36% with an LD50 of 19.5%. The tolerance considered here is of an extreme type (lethality) compared to an intoxication response such as lack of movement (Morgan and Sedensky 1995) or mating ability (Crowder et al. 1996), but is very straightforward to assay and is compatible with many similar studies in Drosophila. Determination of the lethal concentration of wild type worms allows for a simplified screening method for obtaining genetic mutants with higher ethanol tolerances. We are currently in the process of searching for such mutants. We also hope to study the influence of previous exposure to ethanol by contrasting tolerance of naive individuals to that of individuals exposed as larvae. Crowder, C. M., Shebester, L. D., Schedl, T. 1996. Behavioral effects of volatile anesthetics in Caenorhabditis elegans . Anesthesiology 85:901-912. Morgan, P. G., Sedensky, M. M. 1995. Mutations affecting sensitivity to ethanol in the nematode, Caenorhabditis elegans . Alcoholism: Clinical and Experimental Research 19:1423-1429.

Monika Olahova et al. (2007) International Worm Meeting "A 2-Cys peroxiredoxin has stress-specific roles in the response to oxidative stress."

Siavash Khazaipoul, Sarah R. Taylor, Jinling Wang, Kunihiro Matsumoto, Elizabeth A. Veal, Brian A. Morgan, Hideki Inoue, T. Keith Blackwell, Monika Olahova

[International Worm Meeting, 2007]

2-Cys peroxiredoxins (Prxs) are members of a family of ubiquitous thioredoxin peroxidase enzymes whose antioxidant activity has been suggested to play important roles in tumor suppression and carcinogenesis. Recent studies have revealed that, in addition to the detoxification of peroxides, eukaryotic 2-Cys Prxs have important activities as chaperones and redox sensors. For example, in yeast, a 2-Cys Prx is directly involved in the hydrogen peroxide-induced activation of p38 MAPK signaling. The data we will present reveal that the two 2-Cys Prxs, PRDX-2 and PRDX-3, have both distinct and partially overlapping roles in the growth, development, stress responses and longevity of C. elegans. Interestingly, we have identified stress-specific roles for PRDX-2 and PRDX-3. Consistent with a peroxide-protective function for PRDX-2, prdx-2 mutant worms are sensitive to hydrogen peroxide and have a reduced lifespan. However, surprisingly, loss of prdx-2 increases the resistance of C. elegans to arsenic-induced oxidative stress. Our data suggest that the increased arsenite-resistance of the prdx-2 mutant worms is due to increased basal and stress-induced intestinal expression of phase II detoxification genes, such as gcs-1, which protect worms from arsenic-induced stress. Previous work has shown that the stress-activated SEK-1/PMK-1 MAPK signaling pathway regulates gcs-1 expression. Interestingly, our data suggest that PRDX-2 acts either downstream, or by a SEK-1 and PMK-1-independent pathway, to inhibit gcs-1 expression and affect arsenite-resistance. The identification of a mutant with increased resistance to arsenic-induced oxidative stress but reduced hydrogen peroxide resistance suggests that distinct mechanisms are required for tolerance of these different oxidative stress conditions. Furthermore, the reduced lifespan of the arsenite-resistant prdx-2 mutant raises the possibility that peroxide-resistance mechanisms may be more important for longevity.

Elizabeth A Veal et al. (2005) International Worm Meeting "Peroxiredoxins in peroxide-signalling and the response to oxidative stress"

Naoki Hisamoto, Elizabeth A Veal, Kunihiro Matsumoto, Sarah E Milner, T Keith Blackwell, Alison M Day, Stephanie M Bozonet, Brian A Morgan

[International Worm Meeting, 2005]

Cell damage caused by exposure to reactive oxygen species (ROS) eg. peroxide has been linked with the initiation and progression of many diseases, including cancer, diabetes, cardiovascular and autoimmune disease and also with the ageing process. In mammals, ROS are also utilised as second messengers in signal transduction eg. promoting angiogenesis. In eukaryotes, although activation of JNK/p38 mitogen-activated protein kinase (MAPK) signalling pathways and bZip transcription factors is critical for the cellular response to stress, the stress-sensing mechanisms that activate these signalling pathways are not well-understood. However, several, specific, molecular peroxide-sensing mechanisms have recently been identified that regulate peroxide signal transduction through the redox status of key cysteine residues. For example, we have shown that the single 2-Cys peroxiredoxin in the fission yeast Schizosaccharomyces pombe, Tpx1, is a redox sensor with multiple independent roles in peroxide signal transduction. Conserved cysteine residues in Tpx1 are specifically required for the peroxide-induced oxidation and activation of the p38/JNK MAPK, Sty1, and the AP-1-like transcription factor, Pap1. In C.elegans the transcription factor SKN-1 is required to mediate the oxidative stress response. SKN-1 is a distant orthologue of the mammalian Nrf and yeast AP-1-like transcription factors which are required for the expression of many genes involved in detoxification of xenobiotics and ROS. In response to stress SKN-1 accumulates in intestinal nuclei and activates the expression of a phase II detoxification gene, gcs-1, encoding gamma-glutamyl cysteine synthetase heavy chain. Recent work in the Matsumoto lab has shown that SKN-1 is regulated by the MAPK PMK-1. C.elegans contain two 2-Cys peroxiredoxin genes. We have begun to investigate the role of these 2-Cys peroxiredoxins in peroxide-signalling and the oxidative stress response. We have shown that a mutant lacking one of these 2-Cys peroxiredoxins displays increased sensitivity to peroxides. Moreover we have shown that both 2-Cys peroxiredoxins are required for the normal regulation of a gcs-1-gfp reporter. We are currently investigating whether the effects of loss of 2-Cys peroxiredoxin expression on oxidative stress resistance and gcs-1-gfp expression are mediated by effects on PMK-1 and SKN-1 activation.