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[
Trends in Genetics,
2000]
How far down the phylogenic tree should we look for the origins of innate immunity? We know that mammalian cells respond to microbes using Toll-like signalling systems that are remarkably similar in arthropods. Prototypes of these pathways might have arisen in more primitive phyla (initially, perhaps, to regulate development) and their identification would help us to reconstruct the evolution of this facet of immunity. Elements of Toll pathways exist in plants. Does this mean that the last common ancestor of plants, chordates and arthropods, which was a unicellular eukaryote, expressed a Toll-like pathway, or is a similar developmental logic at work in all multicellular life-forms? To address some of these issues we decided to seek a 'worm' Toll pathway, concentrating on the simple and versatile metazoan, Caenorhabditis elegans.
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[
Immunogenetics,
2000]
Toll receptor systems play an important role in our innate immune response to microbial infection (Rock et al. 1998). Studies of related pathways in arthropods (Hoffmann et all. 1999; Imler and Hofmann 2000) have led to key advances in our understanding of these processes. Until recently, however, the possibility that Toll signals may activate both immune and/or developmental pathways in Caenorhabditis elegans has been largely ignored. Early failures to identify Toll receptors or NFB-like transcription factors in the C. elegans genome (Ruvkun and Hobert 1998) let to the assumption that its Toll pathway was inoperable. Therefore, given the paucity of knowledge on innate immune responses for these animals, there was no impetus to develop C. elegans pathogenicity models. Recent database searches, however, have identified components of the elusive C. elegans Toll receptor pathway (Rich et al. 2000; Tan et al. 1999). The existence of a rudimentary immune response is further supported by evidence that antimicrobial peptides are encoded within the C. elegans genome (Tan and Ausubel 2000). In fact, C. elegans is susceptible to infection from several different pathogens, making this genetically tractable invertebrate an attractive model to study host-pathogen interactions. These developments are particularly important for the study of pathogens such as Pseudomonas aeruginosa whose natural hosts include humans. A suitable C. elegans model could, for example, provided a rapid system to screen candidate antibacterial drugs. Consequently, it has now become important to identify and isolate cDNAs for each component of the C. elegans Toll pathway.
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[
International Worm Meeting,
2013]
Organisms face the challenge of distinguishing their own DNA from foreign DNA such as retrotransposons and DNA transposons. This is of particular concern in the germline, where any deleterious effect of transposition can affect all subsequent generations. Small RNAs (e.g. piRNAs) play an important role in identifying and silencing foreign DNA. Here we test a complementary model for silencing transposons in the germline proposed by Fire et al. (2006). In this model, stretches of mostly intronic DNA containing Periodic A/T Clusters (PATCs) identify endogenous genes and promote germline expression by preventing heterochromatic silencing. PATCs are enriched in genes expressed in the germline and residing on autosomal arms, which are strongly enriched for repressive chromatin marks. Do germ cells silence foreign DNA without PATCs by aggressive epigenetic silencing over large genomic regions? We have tested this model by inserting and monitoring germline-expressed transgenes at random genomic locations inside a Mos1 transposon. A transgene without PATCs (Pdpy-30:GFP:H2B) is silenced at all locations outside the central region of autosomes. In contrast, a transgene with PATCs in the promoter (Ppie-1:GFP:H2B) is expressed from a much broader region of the genome: autosome centers, some expression from the arms and a few from the tip of Chr. X. This position based silencing is reproducible; targeted insertions of a Ppie-1 transgene into seven MosSCI sites along Chr. V behave similarly. An endogenous gene (Psmu-1:
smu-1:GFP) with many PATCs is highly resistant to silencing and expressed from essentially all genomic locations, including the entire X chromosome. Does this type of silencing occur naturally and protect worms from foreign DNA? We show that a class of germline specific retrotransposons, Cer1, follow this pattern of silencing by identifying their genomic locations in natural C. elegans isolates. Silenced Cer1 insertions are all integrated into the arms of autosomes or the X-chromosome, whereas most strains with an active Cer1 have at least one copy in the center of an autosome. We think it is likely that PATCs promote germline expression and contribute to distinguishing endogenous genes from foreign DNA.
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Genome Res,
2013]
In metazoans, the nuclear lamina is thought to play an important role in the spatial organization of interphase chromosomes, by providing anchoring sites for large genomic segments named lamina-associated domains (LADs). Some of these LADs are cell-type specific, while many others appear constitutively associated with the lamina. Constitutive LADs (cLADs) may contribute to a basal chromosome architecture. By comparison of mouse and human lamina interaction maps, we find that the sizes and genomic positions of cLADs are strongly conserved. Moreover, cLADs are depleted of synteny breakpoints, pointing to evolutionary selective pressure to keep cLADs intact. Paradoxically, the overall sequence conservation is low for cLADs. Instead, cLADs are universally characterized by long stretches of DNA of high A/T content. Cell-type specific LADs also tend to adhere to this "A/T rule" in embryonic stem cells, but not in differentiated cells. This suggests that the A/T rule represents a default positioning mechanism that is locally overruled during lineage commitment. Analysis of paralogs suggests that during evolution changes in A/T content have driven the relocation of genes to and from the nuclear lamina, in tight association with changes in expression level. Taken together, these results reveal that the spatial organization of mammalian genomes is highly conserved and tightly linked to local nucleotide composition.
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Trends Immunol,
2001]
A current area of interplay between immunologists, geneticists and developmental biologists concerns how Toll receptors assumed their dual roles in pathogen recognition end insect embryo patterning. The development of mechanisms that recognize and control infectious pathogens has been essential for the survival of metazoan organisms. Here, Padraic Fallen and colleagues consider the insights that might be gained from using nematodes to study immune signalling pathways.
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Brain Res Bull,
2001]
Polyglutamine(Q) tract binding protein-1 (PQBP-1) was isolated on the basis of its interaction with polyglutamine tracts and localizes predominantly to the nucleus where it suppresses transcriptional activation by a neuron-specific transcription factor, Brn-2. Its C-terminal domain is highly conserved and binds to a component of the spliceosome. PQBP-1 possesses unique repetitive sequences that may fold as polar zippers. Interestingly, PQBP-1 also forms nuclear inclusion bodies, which are similar to those nucleated by the protein products of polyglutamine disease genes. Furthermore, because PQBP-1 is highly conserved in simple animal metazoans and plants (Caenorhabditis elegans and Arabidopsis), it may perform a basic function in cells. By the same token, disruption of the basic function could be critical to the disease process. Collectively, PQBP-1 might be a candidate molecule involved in the pathology of polyglutamine diseases. In this review, we discuss the structure and function of the PQBP-1 protein, the relevance of its aggregation and possible roles in normal and disease processes.
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J Neurosci,
2003]
Thermotactic behavior in Caenorhabditis elegans is sensitive to both a worm's ambient temperature (T-amb) and its memory of the temperature of its cultivation (T-cult). The AFD neuron is part of a neural circuit that underlies thermotactic behavior. By monitoring the fluorescence of pH-sensitive green fluorescent protein localized to synaptic vesicles, we measured the rate of the synaptic release of AFD in worms cultivated at temperatures between 15 and 25degreesC, and subjected to fixed, ambient temperatures in the same range. We found that the rate of AFD synaptic release is high if either T-amb > T-cult or T-amb > T-cult, but AFD synaptic release is low if T-amb congruent to T-cult. This suggests that AFD encodes a direct comparison between T-amb and T-cult.
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[
Proc Natl Acad Sci U S A,
1988]
The frequency of movement of Tc1, a 1.6-kilobase transposable element in the nematode Caenorhabditis elegans, is under genetic control, and Tc1 insertion sites are widely but nonrandomly distributed. The usually high frequency of insertions at multiple sites in the gene
unc-22 suggested that this gene might be particularly rich in preferred target sites. To discover the features of Tc1 target sites, we have sequenced the sites of seven independent Tc1 transpositions into
unc-22 and three other sites. Our comparison of these and two other sites from the literature indicates that in all cases Tc1 integrates at the dinucleotide T-A when it is flanked both 5' and 3' by particular preferred nucleotides. Our analysis revealed the following consensus target for Tc1 integration: G-A-K-A-T-A-T-G-T, in which K = G or T. This target site sequence specificity has implications both for the mechanism of Tc1 transposition and the use of Tc1 in cloning genes by transposon-tagging.
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BMC Genomics,
2008]
ABSTRACT: BACKGROUND: Studying mitochondrial (mt) genomics has important implications for various fundamental areas, including mt biochemistry, physiology and molecular biology. In addition, mt genome sequences have provided useful markers for investigating population genetic structures, systematics and phylogenetics of organisms. Toxocara canis, Toxocara cati and Toxocara malaysiensis cause significant health problems in animals and humans. Although they are of importance in human and animal health, no information on the mt genomes for any of Toxocara species is available. RESULTS: The sizes of the entire mt genome are 14,322bp for T. canis, 14029bp for T. cati and 14266 bp for T. malaysiensis, respectively. These circular genomes are amongst the largest reported to date for all secernentean nematodes. Their relatively large sizes relate mainly to an increased length in the AT-rich region. The mt genomes of the three Toxocara species all encode 12 proteins, two ribosomal RNAs and 22 transfer RNA genes, but lack the ATP synthetase subunit 8 gene, which is consistent with all other species of Nematode studied to date, with the exception of Trichinella spiralis. All genes are transcribed in the same direction and have a nucleotide composition high in A and T, but low in G and C. The contents of A+T of the complete genomes are 68.57% for T. canis, 69.95% for T. cati and 68.86% for T. malaysiensis, among which the A+T for T. canis is the lowest among all nematodes studied to date. The AT bias had a significant effect on both the codon usage pattern and amino acid composition of proteins. The mt genome structures for three Toxocara species, including genes and non-coding regions, are in the same order as for Ascaris suum and Anisakis simplex, but differ from Ancylostoma duodenale, Necator americanus and Caenorhabditis elegans only in the location of the AT-rich region, whereas there are substantial differences when compared with Onchocerca volvulus, Dirofiliria immitis and Strongyloides stercoralis. Phylogenetic analyses based on concatenated amino acid sequences of 12 protein-coding genes revealed that the newly described species T. malaysiensis was more closely related to T. cati than to T. canis, consistent with results of a previous study using sequences of nuclear internal transcribed spacers as genetic markers. CONCLUSION: The present study determined the complete mt genome sequences for three roundworms of human and animal health significance, which provides mtDNA evidence for the validity of T. malaysiensis and also provides a foundation for studying the systematics, population genetics and ecology of these and other nematodes of socio-economic importance.
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Trends Mol Med,
2007]
Transforming growth factor beta1 (TGFbeta1), an important pleiotropic, immunoregulatory cytokine, uses distinct signaling mechanisms in lymphocytes to affect T-cell homeostasis, regulatory T (T(reg))-cell and effector-cell function and tumorigenesis. Defects in TGFbeta1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. TGFbeta1 prevents abnormal T-cell activation through the modulation of Ca(2+)-calcineurin signaling in a Caenorhabditis elegans Sma and Drosophila Mad proteins (SMAD)3 and SMAD4-independent manner; however, in T(reg) cells, its effects are mediated, at least in part, through SMAD signaling. TGFbeta1 also acts as a pro-inflammatory cytokine and induces interleukin (IL)-17-producing pathogenic T-helper cells (T(h) IL-17 cells) synergistically during an inflammatory response in which IL-6 is produced. Here, we will review TGFbeta1 and its signaling in T cells with an emphasis on the regulatory arm of immune tolerance.