Nathalie Aptel et al. (2002) European Worm Meeting "Mutations in glutamate-gated chloride channel genes affect C. elegans locomotion and fecundity"

Virginia Portillo, Katie Lambert, Alan Cook, Paul Souter, Adrian Wolstenholme, Lindy Holden-Dye, Nathalie Aptel

[European Worm Meeting, 2002]

The glutamate-gated chloride channels (GluCl) are important in human and veterinary medicine as the sites of action of the avermectin/milbemycin group of anthelmintics and insecticides, the best known of which is ivermectin. Ivermectin causes paralysis of worms, suggesting that the GluCl are likely to play a role in locomotion. In C. elegans, five genes (avr-14 &-15 and glc-1, -2 & -3) encode GluCl subunits and at least some of these are widely expressed in the nervous system. We have raised antibodies against the products of all of these genes and are using these to study the distribution of the subunits. So far, we have confirmed that AVR-14B is present in neurones of the motor nervous system. We examined the movement of avr-14 and avr-15 mutants and observed a 50% reduction in the duration of forward movement compared to wild type worms. The avr-14/avr-15 double mutant had an increased reduction compared to either of the single mutants. RNA interference experiments with avr-14 or avr-15 on wild-type worms also reduced the duration of forward movements to a similar extent, confirming that we can use this method to study the effect of reducing expression of genes for which no mutant alleles are yet available. In contrast RNAi with glc- 2, which we have reported to be only expressed in pharyngeal muscle, had no effect on locomotion (Table 1). These effects on the duration of forward movements are the opposite to those obtained with mutants in genes encoding the excitatory glutamate receptors, such as NMR-1, that are expressed on the command interneurones. This raises the possibility that the excitatory and inhibitory glutamate receptors act in an antagonistic fashion to regulate locomotion and we are currently trying to determine if nmr-1 and the GluCl genes are expressed on any of the same neurones.

Snyder, Matthew P. et al. (2013) International Worm Meeting "Turnover of the H3K9me2 Mark During Late Spermatogenesis."

Snyder, Matthew P., Maine, Eleanor, Xu, Xia

[International Worm Meeting, 2013]

Meiotic silencing is a conserved phenomenon targeting unpaired chromosomes and chromosomal regions during prophase of meiosis I. Meiotic silencing in animals typically occurs at the chromatin level and involves accumulation of histone modifications thought to promote a closed chromatin configuration. This chromatin structure may contribute to transcriptional repression and meiotic chromosomal events such as chromosome disjunction (Bean et al 2004, Jaramillo-Lambert and Engebrecht 2010). During meiosis in C. elegans, non-synapsed chromosomes are enriched for H3K9me2 relative to synapsed chromosomes (Kelly et al. 2002; Bean et al. 2004). Such non-synapsed chromosomes include the male X, homologous chromosomes that fail to synapse due to mutation, and chromosomal translocations/duplications. The pattern of H3K9me2 accumulation during meiosis depends on activity of the small RNA machinery, which may have a role in targeting the mark to unpaired chromosomes and ensuring that the mark does not persist abnormally (Maine et al. 2005; She et al. 2009). Taking a combined biochemical/genetic approach, we are identifying additional factors important for regulating H3K9me2 distribution during meiosis. Through this approach, we are identifying genes that appear to be important for turnover of the H3K9me2 mark during late spermatogenesis.

Sandrine Fraboulet et al. (2009) European Worm Neurobiology Meeting "Chemical rescue of paralysis in a transgenic model of Caenorhabditis elegans overexpressing human Beta-amyloid"

Christopher D Link, Mark J Treherne, Andrew K Jones, Steven D Buckingham, Aileen Moloney, David B Sattelle, Hozefa Amijee, David I C Scopes, Sandrine Fraboulet

[European Worm Neurobiology Meeting, 2009]

Authors acknowledge support from MRC. Numerous studies support a role for aggregated Ab as a mediator of the toxicity that underlies Alzheimer.s disease (AD) and other diseases such as Inclusion Body myositis (IBM), an acquired muscle disease affecting people over 50 years old. In this pathology, muscle weakness and degeneration is accompanied by chronic muscle inflammation. Remarkably, despite the inflammation component of the disease, IBM patients are only poorly responsive to anti-inflammatory drugs suggesting that inflammation per se may not be the primary cause of the pathology. We have used a C. elegans transgenic line over-expressing human amyloid 1-42 peptide in the muscles as a model with which to test the efficiency of new compounds on in vivo amyloid toxicity. This C. elegans line becomes paralyzed shortly after the induction of amyloid expression in the muscles, which makes it an easily-recordable phenotype useful for exploring candidate treatments to alleviate the paralysis. We report on the actions of two novel chemicals, which inhibit amyloid aggregation and partially rescue the amyloid-induced phenotype. References: Wu Y, W.Z., Butko P, Christen Y, Lambert MP, Klein WL, Link CD, Luo Y. (2006) J. Neurosci., 26, 13102-13. Link CD, T.A., Kapulkin V, Duke K, Kim S, Fei Q, Wood DE, Sahagan BG. (2003) Neurobiol Aging., 24, 397-413. Jones, A.K., Buckingham, S.D. and Sattelle, D.B. (2005). Nat Rev Drug Discov, 4, 321-30.

Gong, Ting et al. (2021) International Worm Meeting "C. elegans maximize the number of euploid progeny from zim-2 parents with crossover failure on chromosome V."

Tran, Thuy-Linh, McNally, Francis, Gong, Ting

[International Worm Meeting, 2021]

Gametes with incorrect chromosome number can lead to embryonic lethality and developmental deficiency if inherited. Parental trisomy or crossover failure are two conditions expected to yield random meiotic segregation and 25% trisomy among offspring. We previously demonstrated that parental trisomy of the X can be corrected among progeny by preferentially placing the extra chromosome in the first polar body (Cortes, eLife.06056). If 100% efficient, such a univalent elimination mechanism would generate 100% lethal monosomy among progeny of parents with crossover failure. However, high viability rates have been reported among progeny of him-8 mutants (crossover failure on X) (Hodgkin, Genetics 91:67), zim-2 mutants (crossover failure on V) and zim-1 mutants (crossover failure on II and III) (Jaramillo-Lambert, Curr Biol 20:2078), suggesting the possible existence of a distributive segregation mechanism that is more efficient during spermatogenesis than during oogenesis. Here we directly measured the frequency of monosomy, disomy and trisomy among the progeny of zim-1 mutants and zim-2 mutants mated to wild type using PCR polymorphisms that differ between three strain backgrounds. Zim-1 hermaphrodites mated to wild-type males produced 72% disomy II progeny (n=33) and 57% disomy III progeny (n=54). This difference from the 50% expected from random segregation was not significant. Zim-2 hermaphrodites mated with wild-type males produced 73% disomy V progeny (n=65) which was not significantly different than random segregation when corrected for 24% (n=42) crossovers on V observed by counting diakinesis bivalents in oocytes. In striking contrast, zim-2 males mated to wild-type hermaphrodites produced 95% disomy V progeny (n=94) which is significantly higher than random segregation. We are currently testing whether this is due to a high frequency of crossovers on V in zim-2 males, more efficient fertilization by euploid sperm, or a genuine distributive segregation system during male meiosis. A side benefit of our approach is that we can determine the phenotypes of most single chromosome aneuploidies. We have thus far observed monosomies of II, III, or V only in dead embryos and have observed trisomies of II, III, or V only among hatched larvae.

Rocheleau CE et al. (1996) East Coast Worm Meeting "CHARACTERIZATION OF "APX-1 LIKE" MUTANTS IN C.ELEGANS EMBRYOS"

Rocheleau CE, Mello CC

[East Coast Worm Meeting, 1996]

The glp-1 and apx-1 genes encode receptor and ligand respectively, for a cell-cell interaction that specifies the fate of the four cell stage blastomere, ABp. The GLP-1 protein is expressed on the surfaces of sister blastomeres ABa and ABp, and APX-1 is expressed on the surface of the P2 blastomere (Katie Mickie and Jim Priess personal communication). At the four cell stage P2 contacts ABp inducing it to adopt a fate different from its sister cell ABa. The GLP-1 receptor is required again with a different, as yet unidentified, signaling molecule for a second 12-cell stage interaction. GLP-1 and APX-1 have homology to NOTCH and DELTA, receptor and ligand involved in a conserved signaling pathway in Drosophila. The Drosophila suppresser of hairless Su(H) gene encodes a possible transcription factor that represents another conserved component of this signaling pathway. And we have recently confirmed by antisense that a worm Su(H) homolog, yk60c6 (possibly lag-1?), can induce an antisense phenotype identical to that of GLP-1, suggesting that worm Su(H) functions along with glp-1 in both the 4-cell and 12-cell stage interactions. We would like to identify additional genes that are not general components of the signaling pathway but rather function upstream to define the properties of the signaling cell and downstream to define the stage specific outcome of the interaction in the responding cell. In order to identify such genes, we recently screened for new mutations with a phenotype indicating a defect in either the 4-cell or 12-cell stage interaction (but not both). In a screen of 50 thousand haploid genomes we identified seven "apx-1 like" mutants, in which only the 4-cell stage interaction is affected, and five mutations resembling weak glp-1 mutants, in which only the 12-cell stage interaction is defective. So far three of the apx-1 like mutants have been analyzed genetically, and all three represent new mutations in previously known genes, apx-1, glp-1 and skn-2. The new glp-1(ne120) allele is interesting in that it is defective in its function at the four cell stage, but can still function at the twelve cell stage (to our knowledge this is the first glp-1 allele of this type). Skn-2 was known to be required for the P2 cell fate including its ability to signal, however skn-2 was not known to mutate to an Apx like phenotype. Therefore this new allele may indicate a separate more direct function for skn-2 in controlling the signaling properties of P2. We are continuing our genetic and phenotypic analysis of the remaining mutations and plan to do further screening in the near future.