Barry A Chestnut et al. (2003) International Worm Meeting "A genetic screen to isolate suppressors of a temperature-sensitive mutant of the separase gene in C. elegans"

Edward S Davis, Barry A Chestnut, Andy Golden

[International Worm Meeting, 2003]

The anaphase promoting complex or cyclosome (APC/C) drives chromosome segregation during the metaphase-to-anaphase transition in meiosis and mitosis. The APC/C is an E3 ubiquitin ligase that targets proteins for destruction by the 26S proteasome. One key substrate in other organisms is securin, an inhibitor of separase. Separase is the proteolytic enzyme that cleaves the cohesion proteins that hold chromosomes together during metaphase. Degradation of securin by APC/C frees separase so that it has access to the cohesion proteins. The destruction of these cohesion proteins by separase allows anaphase to occur. Siomos et al. (2001) have shown using RNAi and a temperature-sensitive (ts) mutant that the C. elegans separase gene, sep-1, is required for chromosome separation during meiosis I. sep-1 RNAi causes embryonic lethality where chromosomes are not properly separated at meiosis I. DNA replication continues to occur leading to multinucleate 1-cell embryos. In addition, sep-1 L4 larvae shifted to the non-permissive temperature result in sterility. Rose et al. (2002) have identified a protein, IFY-1, that interacts with separase and likely functions as a C. elegans securin. Here we report a suppressor screen using the only existing ts allele of the sep-1 gene. Embryos from sep-1 L4s shifted to the non-permissive temperature show the above meiosis I defects and are lethal. EMS mutagenesis was used to isolate suppressors of the C. elegans sep-1 ts mutant. Three suppressors, av101, av102, and av103 have been isolated that allow growth, survival and fertility at the non-permissive temperature. All three suppressors are semi-dominant. Presently, we are using classical genetics and SNP-snip techniques to map these suppressors. Our characterization of the embryonic lethality and sterility of the sep-1 ts mutant and its suppressors will be reported at the meeting. We anticipate that these suppressor mutations may define proteins that either interact with separase or are meiotic substrates of separas. Siomos et al., 2001. Current Biology 11: 1825-1835. Rose et al., 2002. Current Biology 12: 2118-2123.

Barry A Chestnut et al. (2002) East Coast Worm Meeting "A genetic screen to isolate suppressors of a temperature-sensitive mutation of the separase gene in C. elegans."

Barry A Chestnut, Andy Golden

[East Coast Worm Meeting, 2002]

The anaphase promoting complex or cyclosome (APC/C) drives chromosome segregation during the metaphase-to-anaphase transition in meiosis and mitosis. The APC/C is an E3 ubiquitin ligase that targets proteins for destruction by the 26S proteasome. One key substrate in other organisms is securin, an inhibitor of separase. Separase is the proteolytic enzyme that cleaves the cohesion proteins that hold chromosomes together during metaphase. Degradation of securin by APC/C frees separase so that it has access to the cohesion proteins. The destruction of these cohesion proteins by separase allows anaphase to occur. Siomos et al. (2001) have shown that the C. elegans separase gene, sep-1, is required for chromosome separation during meiosis I. sep-1 RNAi causes embryonic lethality where chromosomes are not properly separated at meiosis I. DNA replication continues to occur leading to multinucleate 1-cell embryos. Here we report a suppressor screen using their temperature-sensitive allele of the sep-1 gene. EMS mutagenesis was used to isolate suppressors in the F2 generation of C. elegans. Presently, three candidate suppressors have been isolated that allow growth and survival at the non-permissive temperature. We anticipate that these suppressor mutations may define proteins that either interact with separase or are meiotic substrates of separase.

Nelson GA et al. (2002) J Radiat Res (Tokyo) "Radiation-induced gene expression in the nematode Caenorhabditis elegans."

Smith AL, Jones TA, Chestnut A, Nelson GA

[J Radiat Res (Tokyo), 2002]

We used the nematode C. elegans to characterize the genotoxic and cytotoxic effects of ionizing radiation in a simple animal model emphasizing the unique effects of charged particle radiation. Here we demonstrate by RT-PCR differential display and whole genome microarray hybridization experiments that gamma rays, accelerated protons and iron ions at the same physical dose lead to unique transcription pro files. 599 of 17871 genes analyzed (3.4%) showed differential expression 3 hrs after exposure to 3 Gy of radiation. 193 were up-regulated, 406 were down-regulated and 90% were affected only by a single species of radiation. A novel statistical clustering technique identified the regulatory relationships between the radiation-modulated genes and showed that genes affected by each radiation species were associated with unique regulatory clusters. This suggests that independent homeostatic mechanisms are activated in response to radiation exposure as a function of track structure or ionization density.

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.