Manuel A Fidalgo et al. (2004) East Coast Worm Meeting "A novel mutant that partially suppresses the daf-2 (e1370) Daf-c phenotype"

Manuel J Munoz, Manuel A Fidalgo

[East Coast Worm Meeting, 2004]

Mutations in the IGF/insulin like receptor daf-2 confer a daf-c phenotype together with an increase of longevity in the adult. Suppressors of the daf-c phenotype of daf-2(e1370) mutant have been isolated. Mutations in the daf-16 or daf-18 genes suppress daf-c phenotype of e1370, making the animal enter to adult. In the other hand, mutations in the daf-12 gene make the e1370 mutant arrest in L2d, a larval stage previous to dauer. We have found a novel mutant (named pv12) that suppresses the daf-c phenotype but they do not let the animal to develop to adult. Most of worms from the daf-2 (e1370); pv12 double showed an L3-L4 arrest. Preliminary result suggest that pv12 works downstream of daf-16 because is enable to relocate the DAF-16 out of the nucleus in an insulin signaling defective mutant background. This new weak suppressor can help to understand how the insulin-signaling pathway regulates dauer formation. The mutant itself is short lived and also has a reduction in the brood size. Mapping and further characterization of this mutant is under progress.

Jose M. Monje et al. (2006) European Worm Meeting "The Role of pkc-1/ttx-4 in Dauer Formation"

Manuel A. Fidalgo, Manuel J. Munoz, Jose M. Monje

[European Worm Meeting, 2006]

The regulation of dauer formation is a complex process. Several genes and different pathways converge in the same point to decide between develop to adult or to the resistant stage known as dauer. Previously, we have isolated the aap-1(m889), a mutant in the regulatory subunit of PIP3 kinase, that enter to dauer constitutively at 27C (Wolkow et al J Biol Chem. 2002 Dec 20). In this work we present the isolation of a suppressor of this phenotype. One of the mutants isolated encodes to PKC-1/TTX-4 a protein kinase C homologue to nPKC-epsilon. PKCs plays important roles in signal transduction.. Our allele of pkc-1 can suppress all the insulin pathway mutants we tested, except daf-2 (e1370). daf-16, a transcription factor downstream of daf-2, goes to the nucleus in the insulin mutants background, but when we look to the daf-16 localization in a double mutant aap-1(m889) pkc-1(pv12), is still nuclear, so our allele suppress the daf-c (dauer formation constitutive) phenotype without relocating daf-16 out of the nucleus, behaving differently to other daf-c suppressors reported. In regards to longevity, pkc-1(pv12) shows a decrease in the lifespan at 25C compare to wild type, but it cannot suppress the long-lived phenotype of all the daf-2 alleles. pv-12 itself is not daf-d. . Surprisingly, pv12 enhances the dauer constitutive formation phenotype of the daf-1 and daf-7 mutants that belong to the TGF-b pathway (a parallel pathway to the IGF/ insulin for dauer formation control). pv-12 itself is not daf-c.. We are investigating if the two antagonist effects of pkc-1 are due to pathway specific roles of this protein in different cell types..

Manuel J Munoz et al. (2002) European Worm Meeting "Positive selection of mutants with increased resistance and longevity."

Manuel A Fidalgo, Donald L Riddle, Manuel J Munoz, Jose M Monje

[European Worm Meeting, 2002]

We developed selective conditions for long-lived mutants by subjecting the first larval stage to thermal stress. At the moment, we have isolated a total of 64 thermotolerant mutants, 50 of them exhibited increased longevity. All the known classes of longevity mutants affected in the dauer signaling pathway were found (Unc, Dyf and Daf-c). 7 of them fail to complement daf-2, 5 age- 1, and 22 unc-31 all of them are known genes involved in the regulation of longevity. We also isolated 2 long-lived alleles of dyf-2 and one of unc-13, those genes were previously identified by other reasons and not related to longevity before. Thirteen additional mutations identified at least four new genes. We call this new mutant class Liv mutants (Long lIved and viable after thermal stress). One of these mutants is liv-6. This mutant resembles the age-1 reference allele, with Daf-c phenotype at 27C, long-lived and similar levels of thermotolerance. age-1 encodes a phosphatidylinositol 3 kinase (PI3K). liv-6 was mapped to the left arm of chromosome I, in the region where the only PI3K adapter subunit worm homologue is located. Sequencing of this gene in the mutant strain and rescue experiments demonstrated that liv-6 encodes for the PI3K adapter subunit.

Ruiz, Manuel (2021) International Worm Meeting "Glucose impacts HSN morphology and induces an egg-laying defective phenotype dependent of the serotonin-signaling pathway"

Ruiz, Manuel

[International Worm Meeting, 2021]

Glucose impacts HSN morphology and induces an egg-laying defective phenotype dependent of the serotonin-signaling pathway Manuel Axel Ruiz and Pamela Padilla Peripheral neuropathy is a common and often painful complication that results from a chronic state of hyperglycemia. In recent years, research has shown that in humans altered levels of serotonin is highly associated to a chronic state of hyperglycemia. Additionally, altered levels of serotonin are associated with various neurological disorders. However, the mechanism by which hyperglycemia impacts serotonin processes is not understood. Here we are using the genetic model system Caenorhabditis elegans as a hyperglycemia model to further understand the impact of a glucose-supplemented diet on the animal's egg-laying behavior. C. elegans possess a nervous system that is composed of 302 neurons. In C. elegans the Hermaphrodite-Specific serotonergic motor Neurons (HSN) play an essential role in regulating egg-laying. Using this model organism, we conducted genetic and cell biological analysis to examine the role a glucose-supplemented diet has on the serotonergic HSN motor neurons. Our preliminary data shows that a glucose-supplemented diet impacts egg-laying and HSN morphology. A significant proportion of animals raised in a glucose-supplemented diet have a higher incidence of intra-uterine egg-hatching, HSN axonal degeneration, and abnormal HSN morphology. We used genetic mutants to dissect out the role the serotonin pathway has on the response to a glucose diet. Furthermore, through RNA-sequencing, we examined how a glucose-supplemented diet alters the expression of genes responsible of serotonergic functions. This work will lead to the further understanding of the molecular mechanisms that are involved on altered serotonergic neuronal functions as a result of a chronic hyperglycemic state.

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.