A missense mutation in
            <i>Caenorhabditis elegans</i>
            prohibitin 2 confers an atypical multidrug resistance

Zubovych, Iryna O.; Doundoulakis, Thomas; Harran, Patrick G.; Roth, Michael G.

doi:10.1073/pnas.0607338103

Cited by 18 publications

(24 citation statements)

References 25 publications

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“…We observed an identical spectrum of defects in animals incubated for 6 hours in liquid or on plates containing 1–4µM HTI-286 or 20µM cryptophycin (Figure S7 and data not shown). Both are potent inhibitors of microtubule polymerization that bind to tubulin at sites distinct from colchicine (Lo et al, 2004; Smith and Zhang, 1996) and show high efficacy in C. elegans (Zubovych et al, 2006). These observations strongly reinforce the conclusion that microtubules are essential for timely homolog pairing.…”

Section: Resultsmentioning

confidence: 99%

Cytoskeletal Forces Span the Nuclear Envelope to Coordinate Meiotic Chromosome Pairing and Synapsis

Sato

Isaac

Phillips

et al. 2009

Cell

266

479

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Summary Sexual reproduction requires the unique cell division called meiosis, in which a diploid cell undergoes a reductional division to generate haploid gametes. A hallmark of meiotic prophase is the formation of pairwise linkages between homologous chromosomes, which later enable them to segregate from each other. In most organisms the pairing of homologous chromosomes is reinforced by synapsis, the polymerization of the synaptonemal complex (SC) between paired chromosome axes. The primary questions addressed here are: 1) how pairing is accomplished and 2) how synapsis is regulated so that it occurs selectively between homologs. We provide evidence that a connection between the chromosomes and the microtubule cytoskeleton via a bridge across the nuclear envelope is critical for both of these mechanisms. Our results indicate the existence of a mechanism that uses dynein to assess homology before licensing SC polymerization. The molecular components of this mechanism are conserved from fungi to mammals.

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Section: Resultsmentioning

confidence: 99%

Cytoskeletal Forces Span the Nuclear Envelope to Coordinate Meiotic Chromosome Pairing and Synapsis

Sato

Isaac

Phillips

et al. 2009

Cell

266

479

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“…We then tested our available coel-1 mutant strains for changes in microtubule function using the microtubule-stabilizing drug paclitaxel (taxol). Eggs hatched on plates containing low doses of paclitaxel arrest their development at larval stages, and the number of animals that escape this arrest to reach adulthood decreases in a dose-dependent manner [17]. All three alleles of coel-1 ( i.e.…”

Section: Resultsmentioning

confidence: 99%

“…Worms were tested for their ability to develop into gravid adults in the presence of the microtubule drug paclitaxel (Sigma, T7191; 10 mM in methanol), essentially as previously described [17] except that worms were grown on solid medium instead of liquid.…”

Section: Methodsmentioning

confidence: 99%

Identification of 526 Conserved Metazoan Genetic Innovations Exposes a New Role for Cofactor E-like in Neuronal Microtubule Homeostasis

et al. 2013

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The evolution of metazoans from their choanoflagellate-like unicellular ancestor coincided with the acquisition of novel biological functions to support a multicellular lifestyle, and eventually, the unique cellular and physiological demands of differentiated cell types such as those forming the nervous, muscle and immune systems. In an effort to understand the molecular underpinnings of such metazoan innovations, we carried out a comparative genomics analysis for genes found exclusively in, and widely conserved across, metazoans. Using this approach, we identified a set of 526 core metazoan-specific genes (the ‘metazoanome’), approximately 10% of which are largely uncharacterized, 16% of which are associated with known human disease, and 66% of which are conserved in Trichoplax adhaerens, a basal metazoan lacking neurons and other specialized cell types. Global analyses of previously-characterized core metazoan genes suggest a prevalent property, namely that they act as partially redundant modifiers of ancient eukaryotic pathways. Our data also highlights the importance of exaptation of pre-existing genetic tools during metazoan evolution. Expression studies in C. elegans revealed that many metazoan-specific genes, including tubulin folding cofactor E-like (TBCEL/coel-1), are expressed in neurons. We used C. elegans COEL-1 as a representative to experimentally validate the metazoan-specific character of our dataset. We show that coel-1 disruption results in developmental hypersensitivity to the microtubule drug paclitaxel/taxol, and that overexpression of coel-1 has broad effects during embryonic development and perturbs specialized microtubules in the touch receptor neurons (TRNs). In addition, coel-1 influences the migration, neurite outgrowth and mechanosensory function of the TRNs, and functionally interacts with components of the tubulin acetylation/deacetylation pathway. Together, our findings unveil a conserved molecular toolbox fundamental to metazoan biology that contains a number of neuronally expressed and disease-related genes, and reveal a key role for TBCEL/coel-1 in regulating microtubule function during metazoan development and neuronal differentiation.

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“…From the foregoing rational, two beta-tubulin inhibitors were included that either showed toxic effects against C. elegans (Taltobulin [78]) or is undergoing clinical trials for use in humans (Combretastatins [79]). To gain additional breadth in anticipated targets, a Rab GTPase inhibitor was included, CID 1067700 [80], because Rab GTPases are apparently involved in cycling of endosomal/exosomal vesicles in C. elegans intestinal cells [53, 54].…”

Section: Methodsmentioning

confidence: 99%

De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells

Jasmer

Rosa

Tyagi

et al. 2019

Preprint

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Efforts to identify new drugs for therapeutic and preventive treatments against parasitic nematodes have gained increasing interest with expanding pathogen omics databases and drug databases from which new anthelmintic compounds might be identified. Here, a novel approach focused on integrating a pan-Nematoda multi-omics data targeted to a specific nematode organ system (the intestinal tract) with evidence-based filtering and chemogenomic screening was undertaken. Based on de novo computational target prioritization of the 3,564 conserved intestine genes in A. suum, exocytosis was identified as a high priority pathway, and predicted inhibitors of exocytosis were tested using the large roundworm (Ascaris suum larval stages), a filarial worm (Brugia pahangi adult and L3), a whipworm (Trichuris muris adult), and the non-parasitic nematode Caenorhabditis elegans. 10 of 13 inhibitors were found to cause rapid immotility in A. suum L3 larvae, and five inhibitors were effective against the three phylogenetically diverse parasitic nematode species, indicating potential for a broad spectrum anthelmintics. Several distinct pathologic phenotypes were resolved related to molting, motility, or intestinal cell and tissue damage using conventional and novel histologic methods. Pathologic profiles characteristic for each inhibitor will guide future research to uncover mechanisms of the anthelmintic effects and improve on drug designs. This progress firmly validates the focus on intestinal cell biology as a useful resource to develop novel anthelmintic strategies.Author summaryThe intestinal cells of parasitic nematodes are not known to regenerate, therefore disruption of essential processes that cause irreparable damage to intestinal cells is expected to promote worm expulsion. To facilitate improved methods of therapy we need to better understand the basic intestinal cell and tissue functions of this critical organ. To that end have undertaken a comprehensive analysis of multi-omics omics data and identify and prioritize intestinal genes/pathways with essential functions and associated drugs and established a foundational model of the STH intestinal system using the large roundworm Ascaris suum to test and validate inhibitors of these functions. We found 10 inhibitors to impacted motility, and seven of those showed severe pathology and an apparent irreparable damage to intestinal cells. Furthermore, five inhibitors were effective against the three phylogenetically diverse parasitic nematode species, indicating potential for a broad spectrum anthelmintics. Our results firmly validate the focus on intestinal cell biology as a useful resource to develop novel anthelmintic strategies.

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A missense mutation in Caenorhabditis elegans prohibitin 2 confers an atypical multidrug resistance

Cited by 18 publications

References 25 publications

Cytoskeletal Forces Span the Nuclear Envelope to Coordinate Meiotic Chromosome Pairing and Synapsis

Cytoskeletal Forces Span the Nuclear Envelope to Coordinate Meiotic Chromosome Pairing and Synapsis

Identification of 526 Conserved Metazoan Genetic Innovations Exposes a New Role for Cofactor E-like in Neuronal Microtubule Homeostasis

De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells

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