A small-molecule screen in C. elegans yields a new calcium channel antagonist

Kwok, Trevor C. Y.; Ricker, Nicole; Fraser, Regina; Chan, Alex Siu Wing; Burns, Andrew R.; Stanley, Elise F.; McCourt, Peter; Cutler, Sean R.; Roy, Peter J.

doi:10.1038/nature04657

Cited by 268 publications

(255 citation statements)

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“…A natural extension of this approach would be to adopt its use within a more highthroughput context, such as a microfluidics or a multiwell plate format. Currently, such high-throughput screens in C. elegans are limited to a single endpoint (i.e., paralysis) (Kwok et al 2006) or death (Petrascheck et al 2007). Screens that provide more detailed phenotypic discrimination would allow the identification of small molecules that exert more specific or subtle effects on locomotion phenotypes caused by either endogenous genetic mutations or transgene-based disease models.…”

Section: Resultsmentioning

confidence: 99%

Biomechanical Profiling of Caenorhabditis elegans Motility

Krajacic¹,

Shen²,

Purohit

et al. 2012

Genetics

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Caenorhabditis elegans locomotion is a stereotyped behavior that is ideal for genetic analysis. We integrated video microscopy, image analysis algorithms, and fluid mechanics principles to describe the C. elegans swim gait. Quantification of body shapes and external hydrodynamics and model-based estimates of biomechanics reveal that mutants affecting similar biological processes exhibit related patterns of biomechanical differences. Therefore, biomechanical profiling could be useful for predicting the function of previously unstudied motility genes.

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Section: Resultsmentioning

confidence: 99%

Biomechanical Profiling of Caenorhabditis elegans Motility

Krajacic¹,

Shen²,

Purohit

et al. 2012

Genetics

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“…Recently, a large-scale small-molecule screen in C. elegans has successfully isolated a calcium channel blocker. Subsequent suppressor genetic screens also identify the α 1 -subunit of the L-type calcium channel as a potential drug target (44). Interestingly, when the mDISC1 transgenic animals were incubated with rolipram, a well-known phosphodiesterase 4 (PDE4)- (13).…”

Section: Discussionmentioning

confidence: 99%

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Chen

Huang

Cheng

2011

Proc. Natl. Acad. Sci. U.S.A.

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Defects in neuronal connectivity of the brain are well documented among schizophrenia patients. Although the schizophrenia susceptibility gene Disrupted-in-Schizophrenia 1 (DISC1) has been implicated in various neurodevelopmental processes, its role in regulating axonal connections remains elusive. Here, a heterologous DISC1 transgenic system in the relatively simple and wellcharacterized Caenorhabditis elegans motor neurons has been established to investigate whether DISC1 regulates axon guidance during development. Transgenic DISC1 in C. elegans motor neurons is enriched in the migrating growth cones and causes guidance defects of their growing axons. The abnormal axonal phenotypes induced by DISC1 are similar to those by gain-of-function rac genes. In vivo genetic interaction studies revealed that the UNC-73/TRIO-RAC-PAK signaling pathway is activated by ectopic DISC1 in C. elegans motor axons. Using in vitro GST pull-down and coimmunoprecipitation assays, we found that DISC1 binds specifically to the amino half of spectrin repeats of TRIO, thereby preventing TRIO's amino half of spectrin repeats from interacting with its first guanine nucleotide exchange factor (GEF) domain, GEF1, and facilitating the recruitment of RAC1 to TRIO. In cultured mammalian cells, RAC1 is activated by increased TRIO's GEF activity when DISC1 is present. These results together indicate that the TRIO-RAC-PAK signaling pathway can be exploited and modulated by DISC1 to regulate axonal connectivity in the developing brain.genetic model | rolipram S chizophrenia is a neurodevelopmental disorder with genetic predispositions (1, 2). Although the etiology and neuropathology of schizophrenia are still elusive, functional and neuroanatomical studies from patients have documented various abnormalities in the diseased brain. In particular, defects in neuronal connectivity during development have been proposed as an important precipitating factor for schizophrenia, which is thought to be unmasked by other developmental events or environmental stressors later in life (3). It is therefore likely that some of the major schizophrenia susceptibility genes are important for regulating axonal connections during development.In recent years, the effort to search for genes susceptible to schizophrenia has led to the identification of the Disrupted-inSchizophrenia 1 (DISC1) gene, whose mutation is highly associated with schizophrenia and other major human mental diseases (4). DISC1 has roles in neuron proliferation, neuron migration, axon outgrowth, and synapse formation/maturation (5-8). In our previous studies, we identified an unexpected role of DISC1 in regulating the guidance of developing axons in the adult-born hippocampal dentate granule cells (5, 9). These effects expand the known functions of DISC1 but sheds little light on how DISC1 effects axon guidance.To systemically study the role of DISC1 in axon guidance and to identify the signaling pathways that might be involved, we set out to establish a heterologous genetic system in the nematode Ca...

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“…Today, a range of molecular phenotyping tools is available to characterize mutations. Although gene expression and protein profiling are predominantly used (3)(4)(5), metabonomic and metabolomic strategies (6, 7) advantageously produce metabolic fingerprints that allow identification of variations in low-molecular-weight compounds in biofluids or organs in response to pathophysiological events (8), drug treatments (9), or genetic polymorphisms (10). It is therefore an attractive hypothesis-free approach for large-scale functional genomics in model organisms (11).…”

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confidence: 99%

Metabotyping of Caenorhabditis elegans reveals latent phenotypes

Blaise

Giacomotto

Elena

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

108

133

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Assigning functions to every gene in a living organism is the next challenge for functional genomics. In fact, 85-90% of the 19,000 genes of the nematode Caenorhabditis elegans genome do not produce any visible phenotype when inactivated, which hampers determining their function, especially when they do not belong to previously characterized gene families. We used 1 H high-resolution magic angle spinning NMR spectroscopy ( 1 H HRMAS-NMR) to reveal the latent phenotype associated to superoxide dismutase (sod-1) and catalase (ctl-1) C. elegans mutations, both involved in the elimination of radical oxidative species. These two silent mutations are significantly discriminated from the wild-type strain and from each other. We identify a metabotype significantly associated with these mutations involving a general reduction of fatty acyl resonances from triglycerides, unsaturated lipids being known targets of free radicals. This work opens up perspectives for the use of 1 H HRMAS-NMR as a molecular phenotyping device for model organisms. Because it is amenable to high throughput and is shown to be highly informative, this approach may rapidly lead to a functional and integrated metabonomic mapping of the C. elegans genome at the systems biology level.functional genomics ͉ metabolic profiling ͉ metabonomics ͉ nuclear magnetic resonance A ssigning functions to every gene in a living organism is the next challenge for functional genomics. However, only a small proportion of genes produce visible phenotypes when inactivated; for example, only 10-15% of the 19,000 genes of the nematode Caenorhabditis elegans produce a visible phenotype (1, 2). For the remaining ones, determining their function is more difficult, especially when they do not belong to previously characterized gene families.For example, oxidative stress is a key, yet subtle, biological process involved in aging, with long-term integration of many slow processes leading to irreversible cellular and molecular damage.Phenotyping plays a critical role in postgenomic sciences. Today, a range of molecular phenotyping tools is available to characterize mutations. Although gene expression and protein profiling are predominantly used (3-5), metabonomic and metabolomic strategies (6, 7) advantageously produce metabolic fingerprints that allow identification of variations in low-molecular-weight compounds in biofluids or organs in response to pathophysiological events (8), drug treatments (9), or genetic polymorphisms (10). It is therefore an attractive hypothesis-free approach for large-scale functional genomics in model organisms (11).Here we capitalize on recent developments in solid-state NMR that allow the acquisition of highly resolved 1 H spectra of metabolites from inhomogeneous materials such as biopsies (12) or food (13). As shown below, when applying 1 H high-resolution magic angle spinning NMR spectroscopy ( 1 H HRMAS-NMR), we provide complex metabolic phenotypes (6) or metabotypes (8) suitable for discriminating between C. elegans oxidative stress mutants, w...

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A small-molecule screen in C. elegans yields a new calcium channel antagonist

Cited by 268 publications

References 25 publications

Biomechanical Profiling of Caenorhabditis elegans Motility

Biomechanical Profiling of Caenorhabditis elegans Motility

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Metabotyping of Caenorhabditis elegans reveals latent phenotypes

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