Vancoppenolle B et al. (1996) European Worm Meeting "Comparison of the early embryonic cell lineage of Caenorhabdi- tis elegans and Pellioditis marina, two rhabditid nematodes."

Borgonie G, Coomans AV, Schnabel R, Vancoppenolle B

[European Worm Meeting, 1996]

The early embryonic cell lineage of Pellioditis marina, a marine rhabditid with relatively short developing time was traced using a 4D-microscope. Although the general pattern of cell divisions is congruent with the lineage described for Caenorhabditis elegans by Sulston and coworkers, striking differences can be observed concerning migrations, timing of divisions and cell deaths. The AB, MS and C lineage of P. marina differ from those of C. elegans both in the occurence of additional cell deaths as wel as in the abscence of certain cell deaths. Additionaly, Caap does not divide in accordance with the characteristic period of the rest of the C lineage. In contrast with C. elegans, the E founder cell in P. marina undergoes a migration before gastrulation and devides into Ea and Ep only after E has entered the interior of the embryo. D and P4 divide in a similar way as in C. elegans.

Vancoppenolle B et al. (1997) International C. elegans Meeting "COMPARISON OF THE EMBRYONIC CELL LINEAGE OF CAENORHABDITIS ELEGANS AND PELLIODITIS MARINA"

Vancoppenolle B, Schnabel R, Coomans AV, Borgonie G

[International C. elegans Meeting, 1997]

The early embryonic cell lineage of Pellioditis marina, a marine rhabditid with relatively short developing time (9hrs at 25!C) was traced using a 4D-microscope. Although the general pattern of cell division is congruent with the lineage described for Caenorhabditis elegans by Sulston and Co-workers, striking differences can be observed concerning migrations, timing of divisions and cell deaths. The AB, MS and C lineage of Pellioditis marina differ from those of Caenorhabditis elegans both in the occurence of additional cell deaths as well as in the abscence of certain cell deaths. Additionaly, Caap does not divide in accordance with the characteristic period for the rest of the C-lineage. In contrast with Caenorhabditis elegans, the E founder cell in Pellioditis marina undergoes a migration before gastrulation and divides into Ea and Ep only after E has entered the interior of the embryo. D and P4 divide in a similar way as in Caenorhabditis elegans.

W Houthoofd et al. (2002) European Worm Meeting "Embryonic development of the free-living, marine nematode Pellioditis marina"

K Jacobsen, G Borgonie, B Vancoppenolle, A Coomans, W Houthoofd

[European Worm Meeting, 2002]

Until now only the embryonic cell lineage of the model organism Caenorhabditis elegans has been described (Sulston et al., 1983). The embryonic cell lineage of the free-living nematode Pellioditis marina has been traced from zygote up until the initiation of muscle contraction by means of 4D-microscopy, marking the second detailed description of the embryonic development of a nematode. P. marina is a close relative of C. elegans, but has adapted to a marine, brackish environment. The overall lineage resembles strongly on that of C. elegans, with a few small differences. The developmental tempo of the early embryogenesis (until division of E cell) is more then two times slower than C. elegans. But the primordial germline cell P4 is already present at the 15-cell stage (in C. elegans at the 24-cell stage). At the stage of muscle contraction (when most cells are established), P. marina has as many cells as C. elegans (571 cells) but less cell deaths (67 and 106 respectively). Tissue conservation varies from highly conserved to highly variable. The intestine, the primordial gonad and the body muscles are highly conserved in the two species, while the pharynx, the epidermis and the nervous system have a more variable configuration. The systematic position of Pellioditis remains unsolved, whether Caenorhabditis or Rhabditis is the closest relative. The early embryogenesis and the developmental timing are comparable with that of other Rhabditis species, while the overall cell lineage is almost identical with that of C. elegans. The latter is a strong argument to place P. marina close to C. elegans in the classification. In more primitive nematodes (like Halicephalobus sp.), sublineages form identical cells, which migrate to their exact location. C. elegans has adjusted these lineages to avoid these migrations (Borgonie et al., 2000). This could explain the chaotic' fate topology in the C. elegans cell lineage. P. marina falls in between: it has already adjusted the Caa-lineage to form two nerve cells, but still has migrations that are avoided in C. elegans.

Marafiga Cordeiro, Larissa et al. (2021) International Worm Meeting "Neuroprotective effects of rutin on ASH neurons in Caenorhabditis elegans model of Huntington's disease"

da Silveira, Tassia, Franzen da Silva, Aline, Arantes, Leticia, Lopes Machado, Marina, Antunes Soares, Felix, Valandro Soares, Marcell, Obetine, Fabiane, Marafiga Cordeiro, Larissa

[International Worm Meeting, 2021]

Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disease. It occurs due to a mutation in the huntingtin gene with an abnormal CAG repeat, leading to a variable length N-terminal polyglutamine chain (poly-Q) which confers toxic functions to mutant Htt leading to neurodegeneration. Rutin is a flavonoid found in plants, buckwheat, some teas and also in apples. Although our previous studies have already indicated that rutin has protective effects in HD's models, more studies are needed to unravel its effects on protein homeostasis and the underlying mechanisms. In our study, we investigated the effects of chronic treatment with rutin in Caenorhabditis elegans model of HD focusing on ASH neurons and antioxidant defense. The synchronized L1 worms were placed on rutin-NGM plates and kept at 20°C. Rutin was added every 24 hours at concentrations of 15, 30, 60 and 120 muM. We assessed octanol response, neuronal polyQ aggregates and dye filling assay. In addition, we analyzed the downstream heat-shock protein-16.2 (HSP-16.2) and superoxide dismutase-3 (SOD-3). Overall, our data demonstrate that chronic rutin treatment maintains the function of ASH neurons in addition to decrease the degeneration of their sensory terminations. The mechanism proposed is antioxidant activity, through the overexpression of antioxidant enzymes and chaperones regulating proteostasis. Our findings provide new evidences about rutin playing a neuroprotective role in C elegans model. In addition to information for treatment strategies for neurodegenerative diseases and other diseases caused by age-related protein aggregation.

Volker Braun et al. (2001) International C. elegans Meeting "Nematode embryonic cell lineages are computationally efficient"

Gaetan Borgonie, Markus Gumbel, Volker Braun, Armand Leroi, Hans-Peter Meinzer, Ricardo Azevedo, Kim Jacobsen, Paul Agapow, Wouter Houthoofd

[International C. elegans Meeting, 2001]

The fixed cell lineages of nematodes like Caenorhabditis elegans are thought to provide a particularly efficient way to build an organism. However, many aspects of the C.elegans embryonic lineage are not obviously efficient (e.g., the distribution of neurons). Here we test whether the embryonic lineages of three species of rhabditid nematodes, C. elegans, Pellioditis marina and Rhabditophanes sp., are computationally efficient in the way cell fates are specified. We define three measures of cell lineage computational efficiency: number of symmetry breaking events, number of determination events and number of sublineages. First, we find that the actual cell lineages of all species specify most cellular phenotypes, such as cell morphology, function, and position in the hatchling, significantly more efficiently than would be expected if these phenotypes were randomly distributed in the same lineage, regardless of the efficiency measure used. Second, we show that the topologies of the actual lineages, themselves, significantly improve the efficiency of cell fate specification compared to cell lineages with random topologies. Third, we find that the cell lineages of the three species, show comparable levels of computational efficiency, despite considerable differences in topology and cell fates assignments. Our results suggest that the embryonic lineages of rhabditid nematodes evolve to place the right cell in the right place in a computationally efficient way.

Teixeira-Castro, A. et al. (2009) International Worm Meeting "Ataxin-3 protein context and cell-specific factors modulate polyQ-mediated neuronal aggregation in a C. elegans model of Machado-Joseph disease."

Morimoto, R., Teixeira-Castro, A., Maciel, P.

[International Worm Meeting, 2009]

Understanding the basis for neuronal subtype-specific protein aggregation is of central importance for several human neurodegenerative diseases, including Machado-Joseph disease. In this study, we developed a novel Ataxin-3 (ATXN3) pathogenesis model in Caenorhabditis elegans and examined the aggregation profile of human ATXN3 by performing FRAP analysis, in live neuronal cells. We found that full-length ATXN3 aggregates only at high Q-length, not found in human patients, whereas C-terminal ATXN3 causes aggregation and neurotoxicity at a threshold length of 75 glutamines. Analysis of specific neurons in C. elegans, reveals that the ventral nerve cord motor neurons are highly affected. Interestingly, certain sensory neurons of the head contain aggregated foci only when the polyQ-stretch is expressed within ATXN3 protein flanking sequences. Moreover, co-expression of full-length human pathological ATXN3 (below aggregation threshold) with an aggregated species capable of initiating the nucleation events, aggravates the aggregation phenotype and new ATXN3-polyQ co-aggregates are formed also in the sensory neurons of these animals, which are not affected when the two species are expressed alone. These results provide direct evidence that protein context and cell-specific factors are major modifiers of polyQ pathogenesis.

Ricardo B R Azevedo et al. (2002) East Coast Worm Meeting "Nematode embryonic cell lineages are computationally efficient"

Wouter Houthoofd, Ute Platzer, Volker Braun, Gaetan Borgonie, Armand M Leroi, Kim Jacobsen, Paul-Michael Agapow, Hans-Peter Meinzer, Ricardo B R Azevedo, Markus Gumbel

[East Coast Worm Meeting, 2002]

What is the minimal amount of information required to specify the cells of a metazoan? Based on ideas from algorithmic information theory and phylogenetics, we develop an algorithm for predicting the distribution of determination events in complete cell lineages. We assume that all such events are either cell autonomous or the outcome of permissive cell-cell interactions, and that the lineage is parsimoniously specified. Applying our algorithm to the complete embryonic lineage of Caenorhabditis elegans, we show that it predicts many known molecular events required to specify cell fates. We then show that less information is required to specify the actual C. elegans lineage than lineages simulated under null models. This is also true for two other species of rhabditid nematode, Pellioditis marina and Rhabditophanes sp., despite many interspecific differences in lineage topology and cell fate assignments. Only one cell fate was found to be inneficiently specified in all species: programmed cell death. Unlike normal cells, most apoptotic cells appear to have no particular function during development. However, we show that the computational efficiency of embryonic development would be increased if cell deaths did not occur all. Thus, selection for increased computational efficiency should lead to a reduction in the number of programmed cell deaths in embryonic cell lineages. Although many programmed cell deaths occur in the C. elegans embryonic lineage (17% of all cells), all of them occur in single-cell monoclones. This is a significantly higher proportion than that expected from permuted lineages and suggests that cell deaths have not accumulated neutrally in the cell lineages of the ancestors of C. elegans. That the absence of cell death monoclones containing two or more cells is due to selection and not due to an intrinsic constraint is demonstrated by the observation that they have been found in other species. Such cases, we suggest, arise frequently, but are then eliminated by reprogramming. Indeed, the main function of somatic cell death in these nematodes might be to eliminate redundant cells over the course of evolution. Our results strongly suggest that selection for computational efficiency moulds the evolution of nematode embryonic cell lineages. But even though nematode lineages are more efficient than random lineages, they are clearly not as efficient as they might be. Why not? The polyclonal origin of some cell fates might be due to the need to generate cells of the same type, such as neurons, in various parts of the embryo. This is supported by the observation that in all species studied here, the majority of cells are born close to their final position in the embryo. We speculate that, in C. elegans, P. marina and Rhabditophanes sp., the fitness cost of repeatedly specifying the same cell type may be less than the cost of additional cell migrations.

Andreia Teixeira-Castro et al. (2008) C.elegans Aging, Stress, Pathogenesis, and Heterochrony Meeting "In vivo dynamics of human ataxin-3 aggregation and neurotoxicity in C. elegans neuronal cells is modulated by Q-length and age"

Andreia Teixeira-Castro, Patricia Maciel, Richard Morimoto

[C.elegans Aging, Stress, Pathogenesis, and Heterochrony Meeting, 2008]

Machado-Joseph disease, like other polyglutamine (polyQ) diseases, is a late onset neurological disorder characterized by the appearance of misfolded protein species, aggregates, neuronal dysfunction and cell death. Although the mechanism(s) underlying the formation of ataxin-3 (AT3) neuronal inclusions are poorly understood, it is becoming increasingly evident that proteolysis of full-length AT3 is a biological relevant event in the disease since it occurs and affects aggregation both in vitro and in vivo. In this study, we developed a new model for AT3 pathogenesis in Caenorhabditis elegans, in which we observed that expression of the full-length human pathogenic AT3 alone did not cause aggregation in live neuronal cells. In contrast, expression of a C-terminal fragment of mutant AT3 resulted in protein aggregation, suggesting that the aggregation-prone fragment was behaving as seed capable of initiating the nucleation events. Moreover, we studied the dynamics of the sequestration process of full-length pathogenic and wild-type AT3 into polyQ aggregates and observed that this process occurs in an age-dependent manner and that there is a tight correlation between aggregation and neuronal toxicity onset. We are currently using this model to address the molecular mechanisms of the ageing-dependence of the aggregation and neurological phenotypes, which could provide clues to the late onset of the human disease.

Andreia Teixeira-Castro et al. (2006) Neuronal Development, Synaptic Function, and Behavior Meeting "Pathological ataxin-3 misfolding in C. elegans neurons"

Patricia Maciel, Richard Morimoto, Andreia Teixeira-Castro

[Neuronal Development, Synaptic Function, and Behavior Meeting, 2006]

Expansion of polyglutamine (polyQ) tracts has been identified as the basis of at least nine neurodegenerative diseases, including Machado-Joseph disease (MJD). MJD is a hereditary ataxia of adult onset caused by expansion of a polyQ tract in ataxin-3 (AT3). AT3 is widely expressed and consists of an N-terminal globular domain with significant helical content, which spans the Josephin domain (JD), and a flexible C-terminal tail containing up to three Ubiquitin interacting motifs (UIM) and the polyQ tract. AT3-induced neurodegeneration affects a specific subset of neurons and is characterized by the presence of AT3- containing protein aggregates. Mutant AT3 forms mainly intranuclear inclusions in diseased human brain as well as in cell culture. Studies suggest that the pathological form of AT3 undergoes a conformational change leading to an alteration in protein homeostasis, misfolding and toxicity. To identify the factors involved in cell-specific pathogenesis observed for MJD, we generated pan-neural Caenorhabditis elegans models expressing chimeric fusion proteins of AT3, with normal and expanded polyQ lengths, tagged on the C-terminus with YFP. We are currently performing the behavioral analysis and looking at the aggregation properties of these models with particular emphasis on polyQ length-dependent aggregation and neurotoxicity. Once we have characterized our model, we will search for genetic modulators of AT3 pathogenesis thus revealing a subset of regulating genes uniquely relevant for mutant AT3 misfolding and toxicity in a metazoan. The comparison to the existing C. elegans polyQ models will contribute significantly in identifying the importance of protein context in cell-specific pathogenesis, providing a better understanding of the disease mechanisms.

Teixeira-Castro, A. et al. (2013) International Worm Meeting "Searching for therapeutic compounds for Machado-Joseph disease: a C. elegans-based screening."

Morimoto, R., Teixeira-Castro, A., Bessa, C., Maciel, P., Jalles, A., Araujo, M., Miranda, A.

[International Worm Meeting, 2013]

Despite the many efforts that are under way to develop therapeutic strategies, no preventive treatment is yet available for any of the polyglutamine diseases. Machado-Joseph disease (MJD) is one of the polyQ disorders caused by the expansion of a polyQ tract within the C-terminal of the ataxin-3 (ATXN3) protein. Mutant ATXN3 acquires the ability to self-associate and enter an aggregation process, which is associated with several pathophysiological consequences for neurons. The lack of therapeutic strategies that effectively prevent neurodegeneration in MJD patients prompted us to search for compounds that modulate mutant ATXN3-related pathogenesis. Recent data from our lab have shown that many aspects of MJD can be properly modeled in the round worm Caenorhabditis elegans. This study is based on the idea that our C. elegans MJD model can be used to perform large-scale drug screenings, in which the identification of effective drugs can be accomplished by looking simultaneously at protein aggregation in the live neuronal cells, and on its impact on neuron-regulated behavior of the whole-animal. Our goal was to screen a library of ~1200 mainly FDA-approved out-of-patent compounds for their ability to prevent or delay the formation of fluorescent mutant ATXN3 aggregates and neurological dysfunction. We excluded the small molecules that were found to be toxic or cause developmental delay to the C. elegans. Ten percent of the non-toxic compounds significantly reduced the locomotion deficits of the animals, three of which made mutant ATXN3 expressing worms perform like wild-type animals in the motility assay. The hits are FDA-approved compounds or are currently in clinical trials for other neurological disorders. We should be able to identify efficacious compounds that can be tested in higher organisms and eventually enter clinical development.