Ahluwalia, Rhea et al. (2021) International Worm Meeting "Discerning the Role of Neuropeptide(s) in C. elegans Thermotaxis Behavior"

Ahluwalia, Rhea, Mori, Ikue, Jang, Moon Sun, Nakano, Shunji

[International Worm Meeting, 2021]

The C. elegans genome encodes over a hundred and fifty neuropeptide genes, which consist of three classes and partake in various functions such as synaptic transmission, cellular signaling and development. Despite their ubiquitous nature, the role(s) played by neuropeptides in several behaviors in C. elegans remains elusive. One such behavioral paradigm is thermotaxis, a robust behavior wherein well-fed worms have been shown to migrate towards the region of past cultivation temperature when placed on a thermal gradient. Studies have suggested the possible involvement of neuropeptides in communication within the neural circuits required for thermotaxis, however, their exact role in thermotaxis regulation is unknown (Narayan, A., Laurent, G. and Sternberg, P. W. (2011) and Nakano, S. et al. (2020)). In order to confirm and further uncover how neuropeptide(s) might be partaking in thermotaxis, we must first identify which neuropeptide(s) are involved for this behavior. To this end, we are performing a genome-wide neuropeptide screen to look for neuropeptide candidates that may be involved in thermotaxis behavior, along with cell-specific knockout for genes crucial for neuropeptide processing in C. elegans. Thus far, we have tested over a hundred mutants, and none have shown strongly altered thermotaxis behavior. In addition, we have tested the four known pro-protein convertases in C. elegans and found that egl-3, the C. elegans ortholog of human proprotein convertase 2 (PCSK 2), displayed abnormal thermotaxis behavior. However, an AFD-specific knockout of egl-3 displayed thermotaxis behavior akin to wildtype, suggesting that egl-3 mediated regulation of thermotaxis most likely takes place through an alternative pathway, prompting further questions pertaining to site of action and the role of the neuropeptides processed by egl-3 in thermotaxis behavior. Altogether, through the genome-wide neuropeptide screen along with the study of the neuropeptide processing enzymes, we hope to gain a holistic insight into peptidergic modulation that controls thermotaxis behavior.

Raimondi, C. et al. (2019) International Worm Meeting "WormJam, a consensus genome-scale metabolic model."

Casanueva, O., Schirra, HJ., Hattwell, J., Witting, M., Raimondi, C.

[International Worm Meeting, 2019]

Caenorhabditis elegans is an important model organism in metabolomics, developmental biology, genetics, and other life science disciplines. With the increasing recognition of metabolism as being of pivotal importance in the study of topics such as ageing, development, disease mechanisms, and evolution, the ability to model metabolism in silico, facilitated by metabolic reconstructions of C. elegans, is important for the characterisation of this organism and its physiological processes. Despite considerable efforts, information on C. elegans metabolism, its genes, proteins, and metabolites is currently scattered across different databases. WormJam (short for Worm Jamboree) is a world-wide community of researchers who aim to rectify this situation by constructing and curating a high-quality consensus genome-scale metabolic model (GSM) of this important biomedical model organism. The resulting WormJam GSM is currently one of the best curated metabolic models for C. elegans. WormJam collaborates with WormBase, the premier repository for C. elegans genes, proteins, phenotypes, and related information, and we have recently started to add metabolite information to this repository. The WormJam model uses the Chemical Entities of Biological Interest (ChEBI) dictionary as primary information/deposition source for metabolite structures, and we have started towards full coverage of the C. elegans GSM with metabolite structures. In addition, we are working on the integration of the Rhea database of biochemical reactions to allow comparison of metabolic reactions between C. elegans and other organisms. Furthermore, we are collaborating with the MetaboLights database to link metabolomics raw and reference data. The availability of the WormJam community-driven consensus reconstruction of C. elegans metabolism will lay the foundation for bringing this important model organism to the forefront of metabolism research.

Hernandez Cravero, Bruno et al. (2021) International Worm Meeting "Uncovering a novel endocannabinoid (2-AG) pathway required to modulate cholesterol metabolism in Caenorhabditis elegans"

Hernandez Cravero, Bruno, De Mendoza, Diego, Prez, Gaston, Vranych , Cecilia

[International Worm Meeting, 2021]

Cholesterol is an essential constituent of eukaryotes membranes and its derivate metabolites also serve as a signaling molecule that is crucial for growth, development and differentiation. Dysregulation of cholesterol metabolism is strongly associated with the development of cardiovascular disorders and neurodegeneration. Caenorhabditis elegans is especially suited to genetically study organismal orchestration of cholesterol metabolism. This worm requires exogenous cholesterol to survive and perturbations in cholesterol trafficking result in an early development larval arrest. Thus, tight regulation of cholesterol storage and distribution within the organism is critical. We have recently demonstrated that the endocannabinoid 2-arachidonoylglycerol (2-AG) plays a key role in C. elegans modulating sterol mobilization (Galles et al, Sci Rep. 2018; 6398). However, the mechanism by which 2-AG controls cholesterol trafficking in C. elegans is not known. Recent reports have shown that C. elegans has two cannabinoid-like receptors named NPR-19 and NPR 32, which are involved in nociception and regenerative axon navigation, respectively (Oakes et al, J. Neurosci. 2017; 2859, Pastuhov et al, Genes Cells. 2016; 696). Here we show that neither NPR-19 or NPR-32 are involved in 2-AG-mediated cholesterol trafficking. Furthermore, we found that the insulin-IGF1(IIS) signalling pathway is essential for the 2-AG suppression of larval arrest induced by cholesterol depletion. Studying the linkage between IIS and 2-AG we found two C. elegans single mutants, ocr-2 and osm-9, were insensitive to the 2-AG-mediated mobilization cholesterol in sterol-depleted worms. OCRs and OSM-9 proteins belong to C. elegans Transient Receptor Potential Vanilloid (TRPV) subfamily channels (Colbert et al, J. Neurosci. 1997; 8259). TRPV channels were previously reported as a sort of cannabinoid receptors in mammals (Ahluwalia et al, Eur J. Neurosci. 2003; 2611). Thus, we propose that OCR-2 and OSM-9 are endocannabinoid receptors in C. elegans, defining a novel signalling pathway mediated by 2-AG that modulates sterol metabolism in C. elegans.