Nichitean, Alexandra M. et al. (2021) International Worm Meeting "Oleic acid modulates reproductive plasticity via DAF-12 in postdauer adults"

Hall, Sarah E., Ow, Maria C., Compere, Frances V., Nichitean, Alexandra M.

[International Worm Meeting, 2021]

Environmental stress experienced during critical periods of development has been shown to result in reproductive plasticity in both plants and animals, although the molecular mechanisms regulating these phenotypes are not well understood. In previous work, we showed that different environmental stresses experienced during early development in Caenorhabditis elegans resulted in distinct reproductive outcomes. C. elegans larva experiencing early-life stress (starvation or high pheromone) may enter the stress resistant, developmentally arrested dauer stage. When environmental conditions improve, larva will exit dauer and proceed with reproductive development (postdauers, PD). We have shown previously that hermaphrodites that experienced starvation-induced dauer (PDStv) exhibited a lower brood size compared to continuously fed animals (control, CON). The set of genes with the most significant differential expression between PDStv and CON adults have functions in fatty acid metabolism, and we found that double mutant combinations of the delta 9-desaturase genes, fat-5, fat-6, and fat-7, as well as mutations in their transcriptional regulators, nhr-49, sbp-1, and mdt-15, abrogated the decreased brood size phenotype. Using Oil Red O staining to examine levels of stored lipids, we found that PDStv adults displayed lower lipid stores in their intestines, but showed increased stored lipids in their embryos, when compared to CON adults. These results suggested that PDStv adults prioritize lipid production for reproduction rather than somatic maintenance after dauer exit. To test this hypothesis, we examined the brood sizes of PDStv adults that were cultivated on OP50 supplemented with different fatty acid molecules. We observed that supplementation with oleic acid (OA) resulted in a significant increase in brood size compared to animals fed only OP50, while other fatty acids resulted in no change or a decrease in brood size. We found that the OA-dependent increase in brood size required FAT-7, as well as the dafachronic acid (DA)-dependent activity of the DAF-12 steroid signaling pathway. Furthermore, we demonstrated that OA is required after dauer exit for the increased brood size phenotype. Together, these results suggest that OA may be acting as a signaling molecule to modulate PDStv reproductive plasticity through regulation of the DA-dependent DAF-12 pathway rather than acting in a nutritional capacity for reproduction.

Ow, M. et al. (2019) International Worm Meeting "Somatic aging pathways regulate reproductive plasticity resulting from early life starvation in Caenorhabditis elegans."

Nichitean, A., Hall, S., Ow, M.

[International Worm Meeting, 2019]

Adult phenotypic plasticity in animals can result from programmed changes in gene expression due to environmental conditions experienced early in development. Stress during the first larval stage in C. elegans can result in animals entering the developmentally arrested, stress resistant dauer stage. Dauer larva can resume development as postdauers (PD) when environmental conditions improve. Previously, we showed that adults that passed through dauer due to starvation (PDStv) exhibited significant changes in gene expression profiles and a decreased brood size compared to animals that experienced continuous development (controls or CON). We also showed that postdauers that experienced crowding (PDPhe) early in development maintained a cellular memory of their early life history that is distinct from PDStv animals, resulting in a unique somatic and germline transcriptional profile and a significant increase in their brood size compared to controls. However, the mechanisms that regulate phenotypic plasticity due to distinct early-life stresses are not well understood. Here, we demonstrate that the endocrine signaling pathways that play principal roles in governing the lifespan of C. elegans adults lacking a functional germ line also serve as a soma-germline signaling mechanism that modulates the reduced fecundity in PDStv adults. We show that key endocrine pathway members, DAF-12/vitamin D receptor homolog, NHR-49/HNF4?, and DAF-16/ FOXO, are required for the reduced brood size of PDStv adults due to their regulation of the onset of germline proliferation as well as the modulation of lipid metabolism. We also find that the germline nuclear RNAi Argonaute HRDE-1 plays a role in reducing the levels of intestinal lipid stores in PDStv adults and in the inheritance of a "starvation memory" from the parental generation to the next. Our results suggest a model whereby endocrine pathways orchestrate signals between somatic and reproductive tissues of PDstv animals to promote reproduction and produce metabolically reprogrammed progeny poised to survive future starvation conditions.

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.