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Wilson RK, Metzstein MM, Ainscough R, Waterston RH, Coulson AR, Craxton M, Thomas K, Dear S, Qiu L, Staden R, Berks M, Halloran N, Thierry-Mieg J, Hillier L, Sulston JE, Du Z, Durbin RM, Hawkins TL, Green P
[
Nature,
1992]
The long-term goal of this project is the elucidation of the complete sequence of the Caenorhabditis elegans genome. During the first year methods have been developed and a strategy implemented that is amenable to large-scale sequencing. The three cosmids sequenced in this initial phase are surprisingly rich in genes, many of which have mammalian homologues.AD - MRC Laboratory of Molecular Biology, Cambridge, UK.FAU - Sulston, JAU - Sulston JFAU - Du, ZAU - Du ZFAU - Thomas, KAU - Thomas KFAU - Wilson, RAU - Wilson RFAU - Hillier, LAU - Hillier LFAU - Staden, RAU - Staden RFAU - Halloran, NAU - Halloran NFAU - Green, PAU - Green PFAU - Thierry-Mieg, JAU - Thierry-Mieg JFAU - Qiu, LAU - Qiu LAU - et al.LA - engPT - Journal ArticleCY - ENGLANDTA - NatureJID - 0410462RN - 0 (Cosmids)SB - IM
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Lau, Tammy, Pho, Kim, Tench, Andrea, McArthur, Andrew, MacNeil, Lesley, Surette, Mike
[
International Worm Meeting,
2021]
Alzheimer's Disease (AD) is the most common neurodegenerative disorder, presently affecting over 46 million people worldwide. The risk of developing Alzheimer's Disease is influenced not only by genetic factors, but also by environment and lifestyle. The multi-factored pathogenesis that leads to AD development poses a challenge for identifying causal factors that promote or protect against neurodegeneration. We use Caenorhabditis elegans as a model of AD to measure the impact of human microbiota species on AD-related phenotypes. Two hallmarks of AD are amyloid-beta (Abeta) plaques and neurofibrillary tangles composed of the protein Tau. Using an Abeta-overexpressing C. elegans model, we identified several bacterial species that differentially impact paralysis, and are characterizing a group of Enterobacteriaceae species that significantly reduce paralysis. To validate these findings, we used another C. elegans model that pan-neuronally expresses Tau protein aggregates. We observed decreased neurodegeneration when the animals were exposed to most of the same bacteria protective against Abeta-induced paralysis, providing additional evidence of microbiota-promoted neuroprotection. To explore these effects, we examined global changes in gene expression in animals exposed to neuroprotective bacteria. We identified several biological processes that were differentially regulated in response to the neuroprotective microbiota species, including innate immunity and protein phosphorylation. C. elegans orthologs of human tau tubulin kinase isoforms, TTBK1 and TTBK2, were down-regulated in response to neuroprotective microbiota species. RNAi-mediated knockdown of C. elegans ttbk genes sufficiently induced neuroprotection in Tau aggregate-prone animals and decreased paralysis in Abeta-overexpressing animals. These findings suggest that bacterial species from the human microbiota can mediate neuroprotection through down-regulation of ttbk. Overall, by studying the impact of the human microbiota on models overexpressing Abeta or aggregate-prone Tau, we have uncovered a potential mechanism by which microbiota-mediated neuroprotection can occur.
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Surette, Michael G., Pho, Kim, Tench, Andrea, Lau, Tammy, MacNeil, Lesley T., McArthur, Andrew G.
[
International Worm Meeting,
2019]
The risk of developing Alzheimer's Disease (AD) is influenced, not only by genetic factors, but also by environment and lifestyle. The multi-factored pathogenesis that leads to AD development poses a challenge for identifying causal factors that promote neurodegeneration. Two hallmarks of AD are amyloid-? (A?) plaques and neurofibrillary tangles composed of the protein Tau. We use Caenorhabditis elegans as a model of AD to measure the impact of human microbiota species on AD-related phenotypes. Using an A?-overexpressing C. elegans model, we identified several bacterial species that differentially impact paralysis and are characterizing a group of Enterobacteriaceae species that significantly reduce paralysis. Most of these bacteria also decreased neurodegeneration in animals that pan-neuronally express aggregate-prone Tau, providing additional evidence of microbiota-promoted neuroprotection. To explore these effects, we examined global changes in gene expression in animals exposed to neuroprotective bacteria. We identified several biological processes that are differentially regulated in response to the neuroprotective microbiota species, including innate immunity and defense response. Overall, by studying the impact of the human microbiota on models overexpressing A? or aggregate-prone Tau, we gain a greater understanding of conserved pathways involved in gene-environment interactions that influence the development of AD.
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[
Genetics,
1999]
Spontaneous mutations were accumulated in 100 replicate lines of Caenorhabditis elegans over a period of approximately 50 generations. Periodic assays of these lines and comparison to a frozen control suggest that the deleterious mutation rate for typical life-history characters in this species is at least 0.05 per diploid genome per generation, with the average mutational effect on the order of 14% or less in the homozygous state and the average mutational heritability approximately 0.0034. While the average mutation rate per character and the average mutational heritability for this species are somewhat lower than previous estimates for Drosophila, these differences can be reconciled to a large extent when the biological differences between these species are taken into consideration.AD - Department of Biology, University of Oregon, Eugene, Oregon 97403, USA.larissa@darkwing.uoregon.eduFAU - Vassilieva, L LAU - Vassilieva LLFAU - Lynch, MAU - Lynch MLA - engID - RO1-GM36827/GM/NIGMSPT - Journal ArticleCY - UNITED STATESTA - GeneticsJID - 0374636SB - IM
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[
Curr Top Dev Biol,
2012]
Noncoding RNAs have emerged as an integral part of posttranscriptional gene regulation. Among that class of RNAs are the microRNAs (miRNAs), which posttranscriptionally regulate target mRNAs containing complementary sequences. The broad presence of miRNAs in lower eukaryotes, plants, and mammals highlights their importance throughout evolution. MiRNAs have been shown to regulate many pathways, including development, and disruption of miRNA function can lead to disease (Ivey and Srivastava, 2010; Jiang et al., 2009). Although the first miRNA genes were discovered in the nematode, Caenorhabditis elegans, almost 20 years ago, the field of miRNA research began when they were found in multiple organisms a little over a decade ago (Lagos-Quintana et al., 2001; Lau et al., 2001; Lee and Ambros, 2001; Lee et al., 1993; Pasquinelli et al., 2000; Wightman et al., 1993). Here, we review one of the first characterized miRNAs,
let-7, and describe its role in development and the intricacies of its biogenesis and function.
-
[
Nat Cell Biol,
2000]
Epithelial cells are polarized, with apical and basal compartments demarcated by tight and adherens junctions. Proper establishment of these subapical junctions is critical for normal development and histogenesis. We report the characterization of the gene
let-413 which has a critical role in assembling adherens junctions in Caenorhabditis elegans. In
let-413 mutants, adherens junctions are abnormal and mislocalized to more basolateral positions, epithelial cell polarity is affected and the actin cytoskeleton is disorganized. The LET-413 protein contains one PDZ domain and 16 leucine-rich repeats with high homology to proteins known to interact with small GTPases. Strikingly, LET-413 localizes to the basolateral membrane. We suggest that LET-413 acts as an adaptor protein involved in polarizing protein trafficking in epithelial cells.AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/ULP, Illkirch, France.FAU - Legouis, RAU - Legouis RFAU - Gansmuller, AAU - Gansmuller AFAU - Sookhareea, SAU - Sookhareea SFAU - Bosher, J MAU - Bosher JMFAU - Baillie, D LAU - Baillie DLFAU - Labouesse, MAU - Labouesse MLA - engSI - GENBANK/AJ276590PT - Journal ArticleCY - ENGLANDTA - Nat Cell BiolJID - 100890575RN - 0 (Helminth Proteins)RN - 0 (LET-413 protein)SB - IM
-
[
Nature,
1993]
gamma-Aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in vertebrates and invertebrates. GABA receptors are the target of anxiolytic, antiepileptic and antispasmodic drugs, as well as of commonly used insecticides. How does a specific neurotransmitter such as GABA control animal behaviour? To answer this question, we identified all neurons that react with antisera raised against the neurotransmitter GABA in the nervous system of the nematode Caenorhabditis elegans. We determined the in vivo functions of 25 of the 26 GABAergic neurons by killing these cells with a laser microbeam in living animals and by characterizing a mutant defective in GABA expression. On the basis of the ultrastructurally defined connectivity of the C. elegans nervous system, we deduced how these GABAergic neurons act to control the body and enteric muscles necessary for different behaviours. Our findings provide evidence that GABA functions as an excitatory as well as an inhibitory neurotransmitter.AD - Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139.FAU - McIntire, S LAU - McIntire SLFAU - Jorgensen, EAU - Jorgensen EFAU - Kaplan, JAU - Kaplan JFAU - Horvitz, H RAU - Horvitz HRLA - engPT - Journal ArticleCY - ENGLANDTA - NatureJID - 0410462RN - 56-12-2 (gamma-Aminobutyric Acid)SB - IM
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[
Science,
2000]
Protein interaction mapping using large-scale two-hybrid analysis has been proposed as a way to functionally annotate large numbers of uncharacterized proteins predicted by complete genome sequences. This approach was examined in Caenorhabditis elegans, starting with 27 proteins involved in vulval development. The resulting map reveals both known and new potential interactions and provides a functional annotation for approximately 100 uncharacterized gene products. A protein interaction mapping project is now feasible for C. elegans on a genome-wide scale and should contribute to the understanding of molecular mechanisms in this organism and in human diseases.AD - Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.FAU - Walhout, A JAU - Walhout AJFAU - Sordella, RAU - Sordella RFAU - Lu, XAU - Lu XFAU - Hartley, J LAU - Hartley JLFAU - Temple, G FAU - Temple GFFAU - Brasch, M AAU - Brasch MAFAU - Thierry-Mieg, NAU - Thierry-Mieg NFAU - Vidal, MAU - Vidal MLA - engID - 1 R21 CA81658 A 01/CA/NCIID - 1 RO1 HG01715-01/HG/NHGRIPT - Journal ArticleCY - UNITED STATESTA - ScienceJID - 0404511RN - 0 (Genetic Vectors)RN - 0 (Helminth Proteins)RN - 0 (LIN-35 protein)RN - 0 (LIN-53 protein)RN - 0 (Repressor Proteins)RN - 0 (Retinoblastoma Protein)SB - IM
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Doucette-Stamm L, Lamesch PE, Reboul J, Temple GF, Hartley JL, Brasch MA, Hill DE, Vaglio P, Thierry-Mieg N, Shin-i T, Lee H, Moore T, Vandenhaute J, Kohara Y, Vidal M, Jackson C, Thierry-Mieg J, Tzellas N, Thierry-Mieg D, Hitti J
[
Nat Genet,
2001]
The genome sequences of Caenorhabditis elegans, Drosophila melanogaster and Arabidopsis thaliana have been predicted to contain 19,000, 13,600 and 25,500 genes, respectively. Before this information can be fully used for evolutionary and functional studies, several issues need to be addressed. First, the gene number estimates obtained in silico and not yet supported by any experimental data need to be verified. For example, it seems biologically paradoxical that C. elegans would have 50% more genes than Drosophilia. Second, intron/exon predictions need to be tested experimentally. Third, complete sets of open reading frames (ORFs), or "ORFeomes," need to be cloned into various expression vectors. To address these issues simultaneously, we have designed and applied to C. elegans the following strategy. Predicted ORFs are amplified by PCR from a highly representative cDNA library using ORF-specific primers, cloned by Gateway recombination cloning and then sequenced to generate ORF sequence tags (OSTs) as a way to verify identity and splicing. In a sample (n=1,222) of the nearly 10,000 genes predicted ab initio (that is, for which no expressed sequence tag (EST) is available so far), at least 70% were verified by OSTs. We also observed that 27% of these experimentally confirmed genes have a structure different from that predicted by GeneFinder. We now have experimental evidence that supports the existence of at least 17,300 genes in C. elegans. Hence we suggest that gene counts based primarily on ESTs may underestimate the number of genes in human and in other organisms.AD - Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.FAU - Reboul, JAU - Reboul JFAU - Vaglio, PAU - Vaglio PFAU - Tzellas, NAU - Tzellas NFAU - Thierry-Mieg, NAU - Thierry-Mieg NFAU - Moore, TAU - Moore TFAU - Jackson, CAU - Jackson CFAU - Shin-i, TAU - Shin-i TFAU - Kohara, YAU - Kohara YFAU - Thierry-Mieg, DAU - Thierry-Mieg DFAU - Thierry-Mieg, JAU - Thierry-Mieg JFAU - Lee, HAU - Lee HFAU - Hitti, JAU - Hitti JFAU - Doucette-Stamm, LAU - Doucette-Stamm LFAU - Hartley, J LAU - Hartley JLFAU - Temple, G FAU - Temple GFFAU - Brasch, M AAU - Brasch MAFAU - Vandenhaute, JAU - Vandenhaute JFAU - Lamesch, P EAU - Lamesch PEFAU - Hill, D EAU - Hill DEFAU - Vidal, MAU - Vidal MLA - engID - R21 CA81658 A 01/CA/NCIID - RO1 HG01715-01/HG/NHGRIPT - Journal ArticleCY - United StatesTA - Nat GenetJID - 9216904SB - IM
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[
Science,
1999]
In many organisms, master control genes coordinately regulate sex-specific aspects of development. SDC-2 was shown to induce hermaphrodite sexual differentiation and activate X chromosome dosage compensation in Caenorhabditis elegans. To control these distinct processes, SDC-2 acts as a strong gene-specific repressor and a weaker chromosome-wide repressor. To initiate hermaphrodite development, SDC-2 associates with the promoter of the male sex-determining gene
her-1 to repress its transcription. To activate dosage compensation, SDC-2 triggers assembly of a specialized protein complex exclusively on hermaphrodite X chromosomes to reduce gene expression by half. SDC-2 can localize to X chromosomes without other components of the dosage compensation complex, suggesting that SDC-2 targets dosage compensation machinery to X chromosomes.AD - Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3204, USA.FAU - Dawes, H EAU - Dawes HEFAU - Berlin, D SAU - Berlin DSFAU - Lapidus, D MAU - Lapidus DMFAU - Nusbaum, CAU - Nusbaum CFAU - Davis, T LAU - Davis TLFAU - Meyer, B JAU - Meyer BJLA - engSI - GENBANK/AF111934ID - GM30702/GM/NIGMSID - T32 GM07127/GM/NIGMSPT - Journal ArticleCY - UNITED STATESTA - ScienceJID - 0404511RN - 0 (Helminth Proteins)RN - 0 (Repressor Proteins)RN - 0 (Sdc-3 protein)RN - 0 (
her-1 protein)SB - IM