Pierre Gonczy (2005) WormBook "Asymmetric cell division and axis formation in the embryo."

Pierre Gonczy

[WormBook, 2005]

Asymmetric cell divisions play an important role in generating diversity during metazoan development. In the early C. elegans embryo, a series of asymmetric divisions are crucial for establishing the three principal axes of the body plan (AP, DV, LR) and for segregating determinants that specify cell fates. In this review, we focus on events in the one-cell embryo that result in the establishment of the AP axis and the first asymmetric division. We first describe how the sperm-derived centrosome initiates movements of the cortical actomyosin network that result in the polarized distribution of PAR proteins. We then briefly discuss how components acting downstream of the PAR proteins mediate unequal segregation of cell fate determinants to the anterior blastomere AB and the posterior blastomere P 1 . We also review how a heterotrimeric G protein pathway generates cortically based pulling forces acting on astral microtubules, thus mediating centrosome and spindle positioning in response to AP polarity cues. In addition, we briefly highlight events involved in establishing the DV and LR axes. The DV axis is established at the four-cell stage, following specific cell-cell interactions that occur between P 2 and EMS , the two daughters of P 1 , as well as between P 2 and ABp , a daughter of AB . The LR axis is established shortly thereafter by the division pattern of ABa and ABp . We conclude by mentioning how findings made in early C. elegans embryos are relevant to understanding asymmetric cell division and pattern formation across metazoan evolution.

Frederick, Pierre-Marc et al. (2017) International Worm Meeting "Characterization of a new Argonaute interactor involved in the miRNA silencing pathway."

Jannot, Guillaume, Simard, Martin J., Frederick, Pierre-Marc, Villoing, Laure, Banville, Isabelle

[International Worm Meeting, 2017]

MicroRNAs are small non-coding RNA who regulates the expression of several genes. The miRNA pathway effector complex, the miRISC (miRNA induced silencing complex), is formed by the association of an argonaute protein with a miRNA. The subsequent binding of the miRISC to its mRNA target can either repress translation or degrade the mRNA. To further understand the miRNA gene regulation mechanisms, it is necessary to characterize new important molecular partners involved in the miRNA silencing. Using different genetic and molecular screens, we identified new miRISC interactors. Among them, we found a DnaJ chaperone protein as an interactor of a C. elegans miRNA-specific Argonaute ALG-1 in the yeast two-hybrid system. Different genetic assays indicate that the DnaJ chaperone is important for the microRNA pathway in animals. Interestingly, observations made with Drosophila cells extract suggested that Heat Shock Proteins or HSPs are required for small RNA loading onto Argonaute proteins (Iwasaki and al, Molecular Cell, 2010). It is also known that DnaJ chaperone proteins can provide specificity to HSPs in order to guide them to specific proteins. We therefore hypothesize that the DnaJ chaperone interacting with ALG-1 recruits HSPs proteins in order to permit loading of miRNAs on this Argonaute. To test this model, we will first demonstrate that DnaJ protein interacts with ALG-1 associated to the loading complex in vivo with the newly generated animals expressing endogenously HA-tagged DNaJ gene. We will next test whether DnaJ is required for: 1) the interaction of HSPs with ALG-1 and; 2) the loading of miRNA onto ALG-1 using both RNAi and KO animals. Taken together, this study will provide mechanistic insights on how microRNA (and potentially others small RNAs in worms) are loaded specifically onto the proper Argonaute proteins.

Jean Pierre Rouault et al. (1999) International C. elegans Meeting "Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN"

Patricia E Kuwabara, Marc Billaud, Olga M Sinilnikova, Danielle Thierry-Mieg, Laurent Duret, Jean Pierre Rouault

[International C. elegans Meeting, 1999]

The tumour suppressor gene PTEN (also called MMAC1 and TEP1) is somatically mutated in a variety of cancer types. In addition, germline mutation of PTEN is responsible for two dominantly-inherited related cancer syndromes called Cowden disease and Bannayan-Ruvalcaba-Riley syndrome. The PTEN gene encodes a dual-specificity phosphatase which inhibits cell spreading and migration partly through the inhibition of the integrin-mediated signalling. Furthermore, PTEN regulates the levels of phosphatidylinositol 3, 4, 5-trisphosphate (PIP3) by specifically dephosphorylating position 3 on the inositol ring. We report here that the dauer formation gene daf-18 is the Caenorhabditis elegans homologue of PTEN. DAF-18 is a component of the insulin-like signalling pathway controlling entry into diapause and adult longevity that is regulated by the DAF-2 receptor tyrosine kinase and the AGE-1 PI3 kinase. We found that the daf-18 (e1375) mutation within the PTEN homologue results in the generation of a premature stop codon. Others have shown that the daf-18 mutation suppresses the life-extension and constitutive dauer formation associated with daf-2 or age-1 mutants. Similarly, we show that inactivation of daf-18 by RNA-mediated interference mimics this suppression, and that a wild type daf-18 transgene rescues the daf-18 dauer defect. These results indicate that the PTEN/DAF-18 antagonizes the DAF-2/AGE-1 pathway, perhaps by catalyzing the dephosphorylation of PIP3 generated by AGE-1. These data further support the notion that mutations of PTEN contribute to the development of human neoplasia through an aberrant activation of the PI3K-Akt/PKB signalling cascade.

Chang JY et al. (2017) Biochim Biophys Acta "Dysregulation of mitophagy in carcinogenesis and tumor progression."

Kim HW, Shong M, Chang JY, Yi HS

[Biochim Biophys Acta, 2017]

The mitochondrial role in carcinogenesis and cancer progression is an area of active research, with many unresolved questions. Various aspects of altered mitochondrial function have been implicated in tumorigenesis and tumor progression, including mitochondrial dysfunction, a metabolic switch to aerobic glycolysis, and dysregulation of mitophagy. Mitophagy is a highly specific quality control process which eliminates dysfunctional mitochondria and promotes mitochondrial turnover, and is involved in the adaptation to nutrient stress by controlling mitochondrial mass. The dysregulation of mitochondrial turnover has both a positive and negative role in cancer. This review will begin with a basic overview of the molecular mechanisms of mitophagy, and highlight recent trends in mitophagy from cancer studies. We will conclude this review by discussing areas of research in normal mitophagy that have yet to be explored in the context of cancer such as mitochondrial proteases, the mitochondrial unfolded protein response, and mitokine action. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.

Virginie Hachet et al. (2006) European Worm Meeting "Centrosomes Dictate Timing of Mitotic Entry in C. elegans Embryos"

Pierre Gonczy, Virginie Hachet

[European Worm Meeting, 2006]

Virginie Hachet and Pierre Gonczy Mitosis is a tightly regulated process that allows equal repartition of the genetic material to daughter cells. Activation of the Cyclin B1/Cdk1 complex is key for initiating entry into mitosis. Intriguingly, in human cells, the active form of Cyclin B1/Cdk1 is detected first at centrosomes, the major microtubule organizing centre (MTOC) of animal cells. However, it is not known in any systems whether centrosomes are required for promoting mitotic entry. We set out to investigate the mechanisms underlying timing of mitotic entry, in the early C. elegans embryo. To this end, we developed a novel assay to monitor timing of mitotic entry with high spatial and temporal resolution. Using this assay, we showed that neither anterior-posterior (A-P) polarity, nor microtubules, dictate timing of mitotic entry. By contrast, we established that centrosome integrity is essential. Moreover, we found that the centrosomal Aurora-A kinase AIR-1 is essential for proper mitotic timing. Finally, by using appropriate mutant embryos, we could demonstrate that centrosomes are not only necessary but also sufficient to promote entry into mitosis. Our findings lead us to propose that centrosomes serve as integrative centres for mitotic regulators and thus dictate the timing of mitotic entry.

Eric G et al. (1995) Worm Breeder's Gazette "MARINER-LIKE ELEMENTS IN THE ENTOMOPARASITIC NEMATODE HETERORHABDITIS BACTERIOPHORA (NEMATODA RHABDITIDA)"

Pierre A, Monique A, Christian L, Eric G

[Worm Breeder's Gazette, 1995]

The mariner transposable element is a small member of the transposable element class II. This element is thought to transpose through a DNA intermediate and shows short inverted terminal repeats (ITR) bordering the entire element. Originally described in Drosophila mauritiana, it has been identified in many other insect species representing ten insect orders. Mariner-like elements (MLE) have also recently been identified in the planarian Dugesia tigrina and in the nematode Caenorhabditis elegans. Using a polymerase chain reaction (PCR) strategy with degenerated oligonucleotides deduced from conserved sequences of the mariner central region, we have been able to detect the presence of MLE in the entomoparasitic nematode Heterorhabditis bacteriophora. These MLE appear to be either deleted forms or full-sized elements of 1279 bp with imperfect ITR of 30 bp. In a full-sized element, the transposase part codes for 358 amino acids including three stop codons and two frame shifts. Therefore, none of the sequences has an open reading frame encoding for a putative transposase. The H. bacteriophora sequences present a 5' transposase longer than those usually described in the Tc/mariner-like family (addition of 14 amino acids). Most of the MLE conserved mariner amino acids (Robertson H.M., 1995, J.Ins.Physiol., 41(2):99) are present and 90% of those missing result from a single nucleotidic mutation. Interestingly, the H. bacteriophora transposase shares more similarities with insect MLE transposase than with C. elegans one. Among the conserved H. bacteriophora amino acids, only 14% are typical C. elegans amino acids (compared with C. elegans PM and C. elegans ZK 370 MLE) while 28% are typical insect ones (compared with Drosophila mauritiana Mos 1 and Hyalophora cecropia MLE). When analysed with Genbank data system, the most important similarity has been found with a Carpelimus sp. mariner (Genbank accession number U04455). The H. bacteriophora MLE is 73% similar, at the nucleotidic level, to this coleopteran MLE, while it is only 52% similar to a C. elegans mariner. On another hand, the H. bacteriophora MLE ITR are more similar to C. elegans MLE ITR (up to 53%) than to insect ones (about 38%). The distribution of H. bacteriophora MLE has been studied by Southern blot analysis. All the tested H. bacteriophora isolates contain MLE, while they seem to be absent from the Steinernema genus, a very closed genus of entomopathogenic nematodes too. These results, together with the fact that H. bacteriophora is an entomoparasitic rhabditid, strongly suggest a case of trans-phyla horizontal transfer. studies are still carried out to further caracterize this new mariner element and to understand the phylogenetic relationships between the mariner transposable elements isolated so far.

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.