Leet, Donna et al. (2015) International Worm Meeting "Investigating the function of HOP-1 presenilin in germ line development."

Goutte, Caroline, Leet, Donna, Hale, Valerie, Brady, Brian

[International Worm Meeting, 2015]

HOP-1 is a presenilin protein that shares 35.4% a.a. identity with the SEL-12 presenilin. The deletion allele hop-1(ar179) does not cause any overt phenotype other than a decrease in brood size. However, in a reduced SEL-12 background, the hop-1(ar179) allele causes classic loss-of-function Notch signaling phenotypes: sterility and maternal-effect lethality. The sterility observed in hop-1; sel-12 double mutants resembles the null phenotype of glp-1 (Notch receptor), in which germ cells fail to proliferate and enter meiosis prematurely. Thus, for the purposes of stimulating mitotic proliferation in the developing gonad, hop-1 and sel-12 are considered redundant. We have analyzed germ line development in hop-1(ar179) hermaphrodites, and demonstrate two different roles for HOP-1: one during larval development when it is co-expressed with SEL-12, and one during adulthood when SEL-12 is no longer present. We analyze several aspects of gonad development in order to monitor the effect of each HOP-1 function. The most dramatic phenotype we observe in hop-1(ar179) mutants is the rapid decline in germ line proliferation during adulthood, demonstrating that adult germ line proliferation is dependent on HOP-1. Other aspects of gametogenesis such as the onset of meiosis, spermatogenesis, and oogenesis are comparable to wild type, as is the amount of sperm produced by hop-1(ar179) animals. We also compare the rate of embryo production and the reproductive span of hop-1(ar179) hermaphrodites to those of wild type animals. Our analysis suggests that under normal conditions HOP-1 functions in the larva to regulate Notch activation levels, and functions in the aging adult to maintain germ cell proliferation. These results provide an explanation for the low brood size of hop-1(ar179) hermaphrodites and provide insight into the interplay of the two presenilins of C. elegans. .

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

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.

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.

Scharf, Andrea et al. (2021) International Worm Meeting "A population state shift supports aging as a cause of adult death"

Tan, Chieh-Hsiang, Scharf, Andrea, Brady, Brian, Wilson, Andrea, Schneider, Daniel, DiAntonio, Gabe, Sanchez, Francesca, Ram, Natasha, Jin, He, Armstead, Brinda, Kocsisova, Zuzana, Kornfeld, Kerry

[International Worm Meeting, 2021]

Birth and death drive population dynamics and determine whether a population survives or is doomed for extinction. Individual traits that influence development, diapause, reproduction, aging and lifespan must impact the age structure and survival of a population. However, the relationships between individual traits and population dynamics are still a major challenge in the emerging field of ecology-development (eco-devo), because wild populations exist in complex ecosystems that are challenging to investigate and undesirable to manipulate. Here, we introduce a laboratory ecosystem based on the model organism C. elegans that can be used to measure and manipulate worm populations over hundreds of generations. To complement this experimental system, we developed a computational simulation that realistically models the ecosystem and makes it possible to monitor the life history of every single worm in the population. With this integrated systems approach, we investigated the role of aging in population dynamics. The first question we addressed was why some populations support old animals whereas, in other populations, all animals die young. We discovered that old age as a cause of death is influenced by three conditions: maximum lifespan, rate of adult culling, and progeny number/food stability. More specifically, the populations displayed an unexpected tipping point for aging as the primary cause of adult death. In populations with high progeny survival and regular starvation almost all adults died young. In contrast, a reduction of progeny survival over the tipping point caused a dramatic shift in the population with the consequence that nearly all adults died of old age. By defining these conditions, we establish a conceptual framework that explains why animals as different as mayflies and elephants die of old age in the wild. In conclusion, we created a powerful experimental platform to investigate the relationships between individual developmental processes, developmental plasticity, and population dynamics including extinction.

Mulcahy B et al. (2010) Invert Neurosci "Meeting report: 2010 Caenorhabditis elegans Neurobiology Meeting, University of Wisconsin, USA."

Mulcahy B, Ient B

[Invert Neurosci, 2010]

Against the backdrop of the scenic Lake Mendota, the C. elegans Neurobiology Meeting came to a head. Expertly organised by Brian Ackley and Bruce Bamber and hosted at the accommodating University of Wisconsin, the meeting brought together recent contributions from many of the major research groups working on the neurobiology of C. elegans. With seven keynote speakers, 57 verbal presentations and hundreds of posters, this exciting event spanned a fascinating 3days from 27 June to 30 June 2010. In keeping with the tradition of this conference, the event on the whole was spearheaded by young investigators from several research institutions. The meeting served to emphasise the gains enjoyed by taking advantage of the genetic tractability of the worm. A thread that ran through the meeting was the importance of integrating data across different levels of biological organisation to permit delineation of the physiology underpinning discrete behavioural states. Recent advances in optogenetics and microfluidics were at the forefront of refining these analyses. The presentations discussed in this meeting report are a selection which reflects this overarching theme.

Harfe BD et al. (1994) Worm Breeder's Gazette "ceh-24, a New NK Class Homeodomain Gene."

Okkema PG, Fire A, Harfe BD

[Worm Breeder's Gazette, 1994]

ceh-24, a new NK class homeodomain gene Brian Harfe 1, 2, Pete Okkema 1, and Andy Fire 1 1 Carnegie Institution of Washington, Department of Embryology, 2 Biology Graduate Program, The Johns Hopkins University The NK class of homeodomain proteins are a set of regulatory factors with a broad evolutionary distribution and a variety of expression patterns. Analysis of pharyngeal myosin regulation led to the identification of a member of this family, ceh-22, which appears to mediate aspects of pharyngeal gene expression (Okkema and Fire, Development 120, 2175). To determine the extent of the NK homeodomain family in C. elegans we have used a degenerate primer based PCR strategy. Among several candidates from the initial PCR, we have so far characterized one gene, denoted ceh-24. The CEH-24 homeodomain falls into the NK class, but is closer to diverse members of the NK family seen in other species than to CEH-22. In addition to the homeodomain, CEH-24 contains an acid activation domain C-terminal to the homeodomain. ceh-24 maps (thanks to Alan Coulson) to chromosome V just left of him-5.

Lee, Inhwan et al. (2013) International Worm Meeting "Epigentic regulation of L1 longevity."

You, Young-jai, Lee, Inhwan

[International Worm Meeting, 2013]

Animals encounter food infrequently and starvation is a common physiological state in their natural circumstance [1]. Hatching in the absence of food, worms arrest their development at the L1 stage and survive starvation more than two weeks [2]. It was shown that adult longevity is regulated epigenetically by chromatin alterations and the genes that regulate epigenetics [3]. Here, we investigate whether L1 longevity is also regulated epigenetically. When we measured various histone modifications using Western blot, we found histone 3 lysine 4 tri-methylation, known to be a modification to activate gene transcription, is increased in L1 starvation. Moreover, mutants of set-2, which encodes a histone 3 lysine 4 tri-methyl transferase that functions in adult longevity [3], has reduced L1 longevity. There are several genes essential for normal L1 longevity, such as aak-2 and daf-16. Based on our data, we hypothesize that chromatin remodeling through histone 3 lysine 4 tri-methylation regulates transcription of genes involved in L1 longevity. Currently we are testing this hypothesis by measuring expression levels these genes by ChIP-qPCR during L1 starvation in set-2 mutant. References [1] Brian H. Lee, Plus Genetics, 2008 [2] Inhwan Lee, Plus One, 2012 [3] Eric L. Greer, Nature, 2010.

Paramita Ray et al. (2004) Mid-west Worm Meeting "ceh-28 is required for feeding in C. elegans"

Peter G Okkema, Paramita Ray

[Mid-west Worm Meeting, 2004]

NK-2 family homeobox genes are important developmental regulators in many organisms. The C. elegans genome contains 4 members of this gene family ( ceh-22, ceh-24, ceh-27 and ceh-28 ). ceh-22 is expressed in the pharyngeal muscles where it regulates gene expression with the pan-pharyngeal factor PHA-4, and we are determining if additional NK-2 family members function similarly in other pharyngeal cell types. Brian Harfe and Andy Fire have previously shown a ceh-28::gfp transcriptional fusion is expressed exclusively in the M4 pharyngeal neuron. We have similarly found a ceh-28::gfp translational fusion containing 3.7 kb of 5' flanking DNA is expressed in M4. Expression initiates during embryogenesis in two cells, and we speculate these cells are M4 and its sister cell, which dies during normal development. We are currently verifying the expression pattern of the endogenous ceh-28 gene using anti-CEH-28 antibodies. M4 is a motor neuron essential for pharyngeal isthmus peristalsis and feeding. To functionally characterize ceh-28 , we have isolated a deletion mutant ceh-28(cu11) . This deletion removes much of the ceh-28 homeobox and is likely a null allele. Homozygous ceh-28(cu11) strains can be maintained, although these mutants appear starved and exhibit slow growth and partially penetrant larval lethality. Similar phenotypes were observed in ceh-28(RNAi) animals. All ceh-28 mutant worms have a stuffed pharynx phenotype similar to animals in which M4 has been killed by laser ablation (Avery and Horvitz, 1987), suggesting M4 is defective. We are currently examining M4 differentiation, morphology and function in ceh-28(cu11) mutants to understand the role of ceh-28 in pharyngeal development.

Wilhelm, Thomas et al. (2015) International Worm Meeting "A C.elegans RNAi screen identifies novel genes with antagonistic pleiotropic effects."

Medina, Rebeca, Wilhelm, Thomas, Richly, Holger, Byrne, Jonathan

[International Worm Meeting, 2015]

In 1957, George C. Williams published the antagonistic pleiotropy hypothesis of aging, which was later mathematically supported by Brian Charlesworth. This theory predicts that some genes mediate beneficial effects early in life when natural selection is strong, but are detrimental late in life when natural selection is weak. Natural selection favors these beneficial effects on fitness early in life at the expense of enriching harmful effects late in life; hence leading to the evolution of aging.We screened 800 chromatin regulators and transcription factors in order to identify novel genes that exhibit antagonistic pleiotropy. Genes were inactivated in the post-reproductive phase by the use of RNAi from day nine of adulthood onwards. The screen led to the identification of several genes that significantly extend lifespan upon late-life inactivation, while shortening lifespan when inactivated early in life.The forkhead box (FOX) A transcription factor pha-4 represents a top candidate of our screen. Late-life inactivation of pha-4 resulted in a strong lifespan extension of 33%. In contrast, inactivation of pha-4 from the first day of adulthood reduced C.elegans lifespan. This is of particular interest, as pha-4 has been shown to mediate diet-restriction and germline-less induced longevity. Our findings indicate that, depending on the age, pha-4 is either needed for normal lifespan and longevity or exhibits detrimental effects. We are currently aiming to identify and to characterize the biological processes underlying the observed negative effects of pha-4 late in life.Generally, genes that behave according to the antagonistic pleiotropy hypothesis may represent promising drug targets to fight age-associated diseases. Our findings emphasize that timing needs to be addressed to fully understand how genes and gene networks impinge on the aging process.