A global analysis of genetic interactions in Caenorhabditis elegans

Abstract We studied the control of pharyngeal excitation in Caenorhabditis elegans. By laser ablating subsets of the pharyngeal nervous system, we found that the MC neuron type is necessary and probably sufficient for rapid pharyngeal pumping. Electropharyngeograms showed that MC transmits excitatory postsynaptic potentials, suggesting that MC acts as a neurogenic pacemaker for pharyngeal pumping. Mutations in genes required for acetylcholine (ACh) release and an antagonist of the nicotinic ACh receptor (nAChR) reduced pumping rates, suggesting that a nAChR is required for MC transmission. To identify genes required for MC neurotransmission, we screened for mutations that cause slow pumping but no other defects. Mutations in two genes, eat-2 and eat-18, eliminated MC neurotransmission. A gain-of-function eat-18 mutation, ad820sd, and a putative loss-of-function eat-18 mutation, ad1110, both reduced the excitation of pharyngeal muscle in response to the nAChR agonists nicotine and carbachol, suggesting that eat-18 is required for the function of a pharyngeal nAChR. Fourteen recessive mutations in eat-2 fell into five complementation classes. We found allele-specific genetic interactions between eat-2 and eat-18 that correlated with complementation classes of eat-2. We propose that eat-18 and eat-2 function in a multisubunit protein complex involved in the function of a pharyngeal nAChR.

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Genetic Interactions Between UNC-17/VAChT and a Novel Transmembrane Protein in Caenorhabditis elegans

Genetics ◽

10.1534/genetics.112.145771 ◽

2012 ◽

Vol 192 (4) ◽

pp. 1315-1325 ◽

Cited By ~ 5

Author(s):

Eleanor A. Mathews ◽

Gregory P. Mullen ◽

Jonathan Hodgkin ◽

Janet S. Duerr ◽

James B. Rand

Keyword(s):

Caenorhabditis Elegans ◽

Transmembrane Protein ◽

Genetic Interactions

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Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans.

Genetics ◽

10.1093/genetics/130.1.105 ◽

1992 ◽

Vol 130 (1) ◽

pp. 105-123 ◽

Cited By ~ 16

Author(s):

J J Vowels ◽

J H Thomas

Keyword(s):

Caenorhabditis Elegans ◽

Genetic Analysis ◽

Single Step ◽

Genetic Interactions ◽

The Other ◽

Environmental Cues ◽

Dauer Larva ◽

Chemosensory Transduction ◽

Dauer Formation ◽

Dauer Larvae

Abstract Dauer larva formation in Caenorhabditis elegans is controlled by chemosensory cells that respond to environmental cues. Genetic interactions among mutations in 23 genes that affect dauer larva formation were investigated. Mutations in seven genes that cause constitutive dauer formation, and mutations in 16 genes that either block dauer formation or result in the formation of abnormal dauers, were analyzed. Double mutants between dauer-constitutive and dauer-defective mutations were constructed and characterized for their capacity to form dauer larvae. Many of the genes could be interpreted to lie in a simple linear epistasis pathway. Three genes, daf-16, daf-18 and daf-20, may affect downstream steps in a branched part of the pathway. Three other genes, daf-2, daf-3 and daf-5, displayed partial or complex epistasis interactions that were difficult to interpret as part of a simple linear pathway. Dauer-defective mutations in nine genes cause structurally defective chemosensory cilia, thereby blocking chemosensation. Mutations in all nine of these genes appear to fall at a single step in the epistasis pathway. Dauer-constitutive mutations in one gene, daf-11, were strongly suppressed for dauer formation by mutations in the nine cilium-structure genes. Mutations in the other six dauer-constitutive genes caused dauer formation despite the absence of functional chemosensory endings. These results suggest that daf-11 is directly involved in chemosensory transduction essential for dauer formation, while the other Daf-c genes play roles downstream of the chemosensory step.

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Faculty Opinions recommendation of A global analysis of Caenorhabditis elegans operons.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1007176.89906 ◽

2002 ◽

Author(s):

Jonathan Hodgkin

Keyword(s):

Caenorhabditis Elegans ◽

Global Analysis

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Uncover Genetic Interactions in Caenorhabditis elegans by RNA Interference

Bioscience Reports ◽

10.1007/s10540-005-2892-7 ◽

2005 ◽

Vol 25 (5-6) ◽

pp. 299-307 ◽

Cited By ~ 8

Author(s):

Angelo Fortunato ◽

Andrew G. Fraser

Keyword(s):

Rna Interference ◽

Caenorhabditis Elegans ◽

Gene Function ◽

Genetic Interactions ◽

Loss Of Function ◽

Future Directions ◽

C Elegans ◽

Genomics Tools ◽

Almost All ◽

Nematode Worm

RNA-mediated interference (RNAi) has emerged recently as one of the most powerful functional genomics tools. RNAi has been particularly effective in the nematode worm C. elegans where RNAi has been used to analyse the loss-of-function phenotypes of almost all predicted genes. In this review, we illustrate how RNAi has been used to analyse gene function in C. elegans as well as pointing to some future directions for using RNAi to examine genetic interactions in a systematic manner.

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A global analysis of Caenorhabditis elegans operons

Nature ◽

10.1038/nature00831 ◽

2002 ◽

Vol 417 (6891) ◽

pp. 851-854 ◽

Cited By ~ 209

Author(s):

Thomas Blumenthal ◽

Donald Evans ◽

Christopher D. Link ◽

Alessandro Guffanti ◽

Daniel Lawson ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Global Analysis

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Synthetic Lethal Genetic Interactions That Decrease Somatic Cell Proliferation in Caenorhabditis elegans Identify the Alternative RFCCTF18 as a Candidate Cancer Drug Target

Molecular Biology of the Cell ◽

10.1091/mbc.e09-08-0699 ◽

2009 ◽

Vol 20 (24) ◽

pp. 5306-5313 ◽

Cited By ~ 23

Author(s):

Jessica McLellan ◽

Nigel O'Neil ◽

Sanja Tarailo ◽

Jan Stoepel ◽

Jennifer Bryan ◽

...

Keyword(s):

Cell Proliferation ◽

Caenorhabditis Elegans ◽

Somatic Cell ◽

Therapeutic Targets ◽

Genetic Interactions ◽

Assay System ◽

Cancer Drug ◽

Mild Phenotype ◽

Synthetic Lethal ◽

C Elegans

Somatic mutations causing chromosome instability (CIN) in tumors can be exploited for selective killing of cancer cells by knockdown of second-site genes causing synthetic lethality. We tested and statistically validated synthetic lethal (SL) interactions between mutations in six Saccharomyces cerevisiae CIN genes orthologous to genes mutated in colon tumors and five additional CIN genes. To identify which SL interactions are conserved in higher organisms and represent potential chemotherapeutic targets, we developed an assay system in Caenorhabditis elegans to test genetic interactions causing synthetic proliferation defects in somatic cells. We made use of postembryonic RNA interference and the vulval cell lineage of C. elegans as a readout for somatic cell proliferation defects. We identified SL interactions between members of the cohesin complex and CTF4, RAD27, and components of the alternative RFCCTF18 complex. The genetic interactions tested are highly conserved between S. cerevisiae and C. elegans and suggest that the alternative RFC components DCC1, CTF8, and CTF18 are ideal therapeutic targets because of their mild phenotype when knocked down singly in C. elegans . Furthermore, the C. elegans assay system will contribute to our knowledge of genetic interactions in a multicellular animal and is a powerful approach to identify new cancer therapeutic targets.

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Caenorhabditis elegans FOS-1 and JUN-1 Regulateplc-1Expression in the Spermatheca to Control Ovulation

Molecular Biology of the Cell ◽

10.1091/mbc.e08-08-0833 ◽

2009 ◽

Vol 20 (17) ◽

pp. 3888-3895 ◽

Cited By ~ 17

Author(s):

Susan M. Hiatt ◽

Holli M. Duren ◽

Y. John Shyu ◽

Ronald E. Ellis ◽

Naoki Hisamoto ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Chromatin Remodeling ◽

Genetic Interactions ◽

Inositol Triphosphate ◽

Activator Protein 1 ◽

Specific Expression ◽

Vulval Development ◽

C Elegans ◽

Physiological Processes ◽

Rate Limiting

Fos and Jun are components of activator protein-1 (AP-1) and play crucial roles in the regulation of many cellular, developmental, and physiological processes. Caenorhabditis elegans fos-1 has been shown to act in uterine and vulval development. Here, we provide evidence that C. elegans fos-1 and jun-1 control ovulation, a tightly regulated rhythmic program in animals. Knockdown of fos-1 or jun-1 blocks dilation of the distal spermathecal valve, a critical step for the entry of mature oocytes into the spermatheca for fertilization. Furthermore, fos-1 and jun-1 regulate the spermathecal-specific expression of plc-1, a gene that encodes a phospholipase C (PLC) isozyme that is rate-limiting for inositol triphosphate production and ovulation, and overexpression of PLC-1 rescues the ovulation defect in fos-1(RNAi) worms. Unlike fos-1, regulation of ovulation by jun-1 requires genetic interactions with eri-1 and lin-15B, which are involved in the RNA interference pathway and chromatin remodeling, respectively. At least two isoforms of jun-1 are coexpressed with fos-1b in the spermatheca, and different AP-1 dimers formed between these isoforms have distinct effects on the activation of a reporter gene. These findings uncover a novel role for FOS-1 and JUN-1 in the reproductive system and establish C. elegans as a model for studying AP-1 dimerization.

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