Lord , A. et al. (2019) International Worm Meeting "TXBP-3 regulates C. elegans cell adhesion and spermathecal contractility."

Cram, Erin, Zaidel-Bar, Ronen, Lord , A.

[International Worm Meeting, 2019]

Proteins containing PDZ domains function primarily as molecular scaffolds that recruit target proteins in order to promote cell signaling, cell adhesion, and protein scaffolding. TAX1BP3 is a highly conserved protein with a single atypical PDZ domain. Little is known about the C. elegans homolog, TXBP-3, although it has been shown to interact with the FERM family protein NFM-1/merlin. TXBP-3 is expressed in the pharynx, vulval precursor cells, spermatheca, and rectal epithelial cells of C. elegans. The current study investigates the role of TXBP-3 in the spermatheca as a model for understanding the coordination of contractility in a tube and to elucidate the function of TXBP-3 in the regulation of anchoring proteins, such as actin, to the cytoskeleton. TXBP-3 relocalizes from the apical to the basal surface of the spermatheca upon ovulation of oocytes into the spermatheca. Overexpression of TXBP-3 results in more rapid embryo transit times during the first three ovulations, which may be caused by a downstream effect on RHO-1, a major contributor to spermathecal contractility. Previous research indicates that TAX1BP3 is necessary for the redistribution of Rhotekin, a Rho GTPase effector that is conserved in C. elegans, which suggests a potential role of TXBP-3 in the regulation of this important pathway. We also demonstrate that CRISPR deletion of a coding region of TXBP-3 results in slower transit times and causes a "lace nose" phenotype, where the worm appears to have large vacuoles along both sides of the nose, possibly due to mis-localization of anchoring proteins. We aim to characterize the TXBP-3 gene and identify its interactors in order to better understand how it affects cytoskeletal organization and cell signaling.

Lord CE et al. (2012) Eur J Cell Biol "Programmed cell death in C. elegans, mammals and plants."

Gunawardena AH, Lord CE

[Eur J Cell Biol, 2012]

Programmed cell death (PCD) is the regulated removal of cells within an organism and plays a fundamental role in growth and development in nearly all eukaryotes. In animals, the model organism Caenorhabditis elegans (C. elegans) has aided in elucidating many of the pathways involved in the cell death process. Various analogous PCD processes can also be found within mammalian PCD systems, including vertebrate limb development. Plants and animals also appear to share hallmarks of PCD, both on the cellular and molecular level. Cellular events visualized during plant PCD resemble those seen in animals including: nuclear condensation, DNA fragmentation, cytoplasmic condensation, and plasma membrane shrinkage. Recently the molecular mechanisms involved in plant PCD have begun to be elucidated. Although few regulatory proteins have been identified as conserved across all eukaryotes, molecular features such as the participation of caspase-like proteases, Bcl-2-like family members and mitochondrial proteins appear to be conserved between plant and animal systems. Transgenic expression of mammalian and C. elegans pro- and anti-apoptotic genes in plants has been observed to dramatically influence the regulatory pathways of plant PCD. Although these genes often show little to no sequence similarity they can frequently act as functional substitutes for one another, thus suggesting that action may be more important than sequence resemblance. Here we present a summary of these findings, focusing on the similarities, between mammals, C. elegans, and plants. An emphasis will be placed on the mitochondria and its role in the cell death pathway within each organism. Through the comparison of these systems on both a cellular and molecular level we can begin to better understand PCD in plant systems, and perhaps shed light on the pathways, which are controlling the process. This manuscript adds to the field of PCD in plant systems by profiling apoptotic factors, to scale on a protein level, and also by filling in gaps detailing plant apoptotic factors not yet amalgamated within the literature.

Zaarur N et al. (2019) Mol Metab "ATGL-1 mediates the effect of dietary restriction and the insulin/IGF-1 signaling pathway on longevity in C.elegans."

Lord A, Zaarur N, Grishok A, Mackenzie J, Kandror KV, Desevin K

[Mol Metab, 2019]

OBJECTIVE: Animal lifespan is controlled through genetic pathways that are conserved from nematodes to humans. Lifespan-promoting conditions in nematodes include fasting and a reduction of insulin/IGF signaling. Here we aimed to investigate the input of the Caenorhabditis elegans homologue of the mammalian rate-limiting lipolytic enzyme Adipose Triglyceride Lipase, ATGL-1, in longevity control. METHODS: We used a combination of genetic and biochemical approaches to determine the role of ATGL-1 in accumulation of triglycerides and regulation of longevity. RESULTS: We found that expression of ATGL is increased in the insulin receptor homologue mutant daf-2 in a FoxO/DAF-16-dependent manner. ATGL-1 is also up-regulated by fasting and in the eat-2 loss-of-function mutant strain. Overexpression of ATGL-1 increases basal and maximal oxygen consumption rate and extends lifespan in C.elegans. Reduction of ATGL-1 function suppresses longevity of the long-lived mutants eat-2 and daf-2. CONCLUSION: Our results demonstrate that ATGL is required for extended lifespan downstream of both dietary restriction and reduced insulin/IGF signaling.

Bai X et al. (2020) Elife "Caenorhabditis elegans PIEZO channel coordinates multiple reproductive tissues to govern ovulation."

Brugman K, Cram EJ, Sternberg PW, Bouffard JW, Bai X, Lord A, Golden A

[Elife, 2020]

PIEZO1 and PIEZO2 are newly identified mechano-sensitive ion channels that exhibit a preference for calcium in response to mechanical stimuli. In this study, we discovered the vital roles of <i>pezo-1</i>, the sole <i>PIEZO</i> ortholog in <i>C. elegans,</i> in regulating reproduction. A number of deletion alleles as well as a putative gain-of-function mutant of PEZO-1 caused a severe reduction in brood size. <i>In vivo</i> observations showed that oocytes undergo a variety of transit defects as they enter and exit the spermatheca during ovulation. Post ovulation oocytes were frequently damaged during spermathecal contraction. However, the calcium signaling was not dramatically changed in the <i>pezo-1</i> mutants during ovulation. Loss of PEZO-1 also revealed an inability of self-sperm to properly navigate back to the spermatheca after being pushed out of the spermatheca during ovulation. These findings suggest that PEZO-1 acts in different reproductive tissues to promote proper ovulation and fertilization in <i>C. elegans</i>.

Esse R et al. (2019) RNA "DOT1L complex suppresses transcription from enhancer elements and ectopic RNAi in Caenorhabditis elegans."

Esse R, Gushchanskaia ES, Lord A, Grishok A

[RNA, 2019]

Methylation of histone H3 on lysine 79 (H3K79) by DOT1L is associated with actively transcribed genes. Earlier, we described that DOT-1.1, the Caenorhabditis elegans homologue of mammalian DOT1L, cooperates with the chromatin-binding protein ZFP-1 (AF10 homologue) to negatively modulate transcription of highly and widely expressed target genes. Also, reduction of ZFP-1 levels has consistently been associated with lower efficiency of RNA interference (RNAi) triggered by exogenous double-stranded RNA (dsRNA), but the reason for this is not clear. Here, we demonstrate that the DOT1L complex suppresses transcription originating from enhancer elements and antisense transcription, thus potentiating expression of enhancer-regulated genes. We also show that worms lacking H3K79 methylation do not survive and this lethality is suppressed by mutations in caspase-3, and Dicer complex components that initiate gene silencing response to exogenous dsRNA. Our results suggest that ectopic elevation of endogenous dsRNA directly or indirectly resulting from global misregulation of transcription in DOT1L complex mutants may engage the Dicer complex and, therefore, limit the efficiency of exogenous RNAi.

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.