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Zipperlen, Peder; Nairz, Knud; Rimann, Ivo; Basler, Konrad; Hafen, Ernst; Hengartner, Michael O.; Hajnal, Alex

doi:10.1186/gb-2005-6-2-r19

Cited by 22 publications

(11 citation statements)

References 43 publications

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“…We screened approximately 11’000 genomes for each of the two approaches. Isolated candidates were mapped using fragment length polymorphisms (FLPs) as described by 42 either until the phenotypically relevant mutation was found or until intervals were small enough to use arrayCGH [44] or whole genome sequencing [45] for detection of the mutation. We isolated a total of 14 candidates from the two screens and for all but four of these the relevant mutation could be identified (Table 1).…”

Section: Resultsmentioning

confidence: 99%

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A Network of HSPG Core Proteins and HS Modifying Enzymes Regulates Netrin-Dependent Guidance of D-Type Motor Neurons in Caenorhabditis elegans

et al. 2013

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Heparan sulfate proteoglycans (HSPGs) are proteins with long covalently attached sugar side chains of the heparan sulfate (HS) type. Depending on the cellular context HS chains carry multiple structural modifications such as sulfate residues or epimerized sugars allowing them to bind to a wide range of molecules. HSPGs have been found to play extremely diverse roles in animal development and were shown to interact with certain axon guidance molecules. In this study we describe the role of the Caenorhabditis elegans HSPG core proteins Syndecan (SDN-1) and Glypican (LON-2) and the HS modifying enzymes in the dorsal guidance of D-type motor axons, a process controlled mainly by the conserved axon guidance molecule UNC-6/Netrin. Our genetic analysis established the specific HS code relevant for this axon guidance event. Using two sensitized genetic backgrounds, we isolated novel components influencing D-type motor axon guidance with a link to HSPGs, as well as new alleles of several previously characterized axon guidance genes. Interestingly, the dorsal axon guidance defects induced by mutations in zfp-1 or lin-35 depended on the transgene oxIs12 used to visualize the D-type motor neurons. oxIs12 is a large multi-copy transgene that enlarges the X chromosome by approximately 20%. In a search for genes with a comparable phenotype we found that a mutation in the known dosage compensation gene dpy-21 showed similar axon guidance defects as zfp-1 or lin-35 mutants. Thus, derepression of genes on X, where many genes relevant for HS dependent axon guidance are located, might also influence axon guidance of D-type motor neurons.

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Section: Resultsmentioning

confidence: 99%

“…Mutants (generated in the Bristol N2 background) were crossed to animals of the Hawaii (CB4856) background and the mutations mapped using fragment length polymorphism (FLP) mapping as described by 42. Following FLP mapping, we used three distinct strategies to identify candidate genes.…”

Section: Methodsmentioning

confidence: 99%

A Network of HSPG Core Proteins and HS Modifying Enzymes Regulates Netrin-Dependent Guidance of D-Type Motor Neurons in Caenorhabditis elegans

et al. 2013

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“…coli plates, and the F 2 generation was screened for CCL2-resistant worms. Mutations were mapped to chromosomes using fragment-length polymorphisms (FLP) mapping Tier 1 [ 62 ]. As all mutations mapped to chromosomes II, III, and IV, which also carry the fut-1 , ger-1 , and bre-1 genes, respectively, we PCR amplified and sequenced the genome locus (exons and introns) of the relevant candidate gene for each mutant.…”

Section: Methodsmentioning

confidence: 99%

Disruption of the C. elegans Intestinal Brush Border by the Fungal Lectin CCL2 Phenocopies Dietary Lectin Toxicity in Mammals

et al. 2015

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Lectins are non-immunoglobulin carbohydrate-binding proteins without enzymatic activity towards the bound carbohydrates. Many lectins of e.g. plants or fungi have been suggested to act as toxins to defend the host against predators and parasites. We have previously shown that the Coprinopsis cinerea lectin 2 (CCL2), which binds to α1,3-fucosylated N-glycan cores, is toxic to Caenorhabditis elegans and results in developmental delay and premature death. In this study, we investigated the underlying toxicity phenotype at the cellular level by electron and confocal microscopy. We found that CCL2 directly binds to the intestinal apical surface and leads to a highly damaged brush border with loss of microvilli, actin filament depolymerization, and invaginations of the intestinal apical plasma membrane through gaps in the terminal web. We excluded several possible toxicity mechanisms such as internalization and pore-formation, suggesting that CCL2 acts directly on intestinal apical plasma membrane or glycocalyx proteins. A genetic screen for C. elegans mutants resistant to CCL2 generated over a dozen new alleles in bre 1, ger 1, and fut 1, three genes required for the synthesis of the sugar moiety recognized by CCL2. CCL2-induced intestinal brush border defects in C. elegans are similar to the damage observed previously in rats after feeding the dietary lectins wheat germ agglutinin or concanavalin A. The evolutionary conserved reaction of the brush border between mammals and nematodes might allow C. elegans to be exploited as model organism for the study of dietary lectin-induced intestinal pathology in mammals.

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“…(C) Genotypes and phenotypes of the let-60(gf) miRILs sorted by increasing VI. Genotypes determined by FLP mapping [ 15 ] are plotted on the y-axis versus the miRIL numbers on the x-axis. Hawaii genotypes are indicated with red, Bristol genotypes with blue and missing genotypes with gray colors.…”

Section: Introductionmentioning

confidence: 99%

“…In each of the panels showing chromosomes I through X, the locations of the FLP markers used for genotyping are indicated on the x-axis with vertical lines. For the exact locations of the FLPs used, see Materials and Methods and [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA

et al. 2015

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Human cancer is caused by the interplay of mutations in oncogenes and tumor suppressor genes and inherited variations in cancer susceptibility genes. While many of the tumor initiating mutations are well characterized, the effect of genetic background variation on disease onset and progression is less understood. We have used C. elegans genetics to identify genetic modifiers of the oncogenic RAS/MAPK signaling pathway. Quantitative trait locus analysis of two highly diverged C. elegans isolates combined with allele swapping experiments identified the polymorphic monoamine oxidase A (MAOA) gene amx-2 as a negative regulator of RAS/MAPK signaling. We further show that the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), which is a product of MAOA catalysis, systemically inhibits RAS/MAPK signaling in different organs of C. elegans. Thus, MAOA activity sets a global threshold for MAPK activation by controlling 5-HIAA levels. To our knowledge, 5-HIAA is the first endogenous small molecule that acts as a systemic inhibitor of RAS/MAPK signaling.

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Cited by 22 publications

References 43 publications

A Network of HSPG Core Proteins and HS Modifying Enzymes Regulates Netrin-Dependent Guidance of D-Type Motor Neurons in Caenorhabditis elegans

A Network of HSPG Core Proteins and HS Modifying Enzymes Regulates Netrin-Dependent Guidance of D-Type Motor Neurons in Caenorhabditis elegans

Disruption of the C. elegans Intestinal Brush Border by the Fungal Lectin CCL2 Phenocopies Dietary Lectin Toxicity in Mammals

Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA

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