Bazopoulou MD et al. (2004) Focus on Protein Research "Protein turnover and ageing."

Bazopoulou MD, Troullinaki K, Tavernarakis N

[Focus on Protein Research, 2004]

To MD et al. (2006) Oncogene "Functional characterization of novel presenilin-2 variants identified in human breast cancers."

Gokgoz N, Bernstein A, To MD, Hyslop PS, Doyle TG, Knight JA, Donoviel DB, Andrulis IL

[Oncogene, 2006]

We identified in breast cancer cases two germline alterations, R62H and R71W, in presenilin-2 (PS-2), a gene involved in familial Alzheimer''s disease (FAD). The role of these alleles in FAD is unclear, but neither allele affected Abeta(42)/Abeta(40) ratio. However, both R62H and R71W alterations compromised PS-2 function in Notch signaling in Caenorhabditis elegans and cell growth inhibition in mouse embryonic fibroblasts, and these effects were dependent on gene dosage. We found that both alterations enhanced the degradation of the PS-2 full-length protein, indicating that they may have a loss-of function effect. The effect of the R71W alteration was noticeably stronger, and we observed an almost threefold higher frequency of this allele in breast cancer cases versus controls, but this difference did not reach statistical significance. Nonetheless, these results collectively suggest that the novel PS-2 alleles described here, especially R71W, affect PS-2 function and may potentially confer a moderate risk of susceptibility to breast cancer.Oncogene advance online publication, 13 February 2006; doi:10.1038/sj.onc.1209397.

Yandell MD et al. (1994) Worm Breeder's Gazette "ceg-1 is Very Similar to decapentaplegic."

Wood WB, Yandell MD

[Worm Breeder's Gazette, 1994]

CEG-I IS VERY SIMILAR TO DECAPENTAPLEGIC Mark Yandell and Bill Wood Department of MCD Biology, University of Colorado, Boulder We have cloned a TGF-beta homolog which we have provisionally called ceg-l for C. elegans growth factor-l. ceg-l is a member of the dpp/bmp2-4 subclassl of TGF-beta proteins (see PILEUP diagram) and is very similar to the Drosophila gene decapentaplegic (dpp) and the mouse gene GDF-5, the product of the brachypodism locus, alleles of which cause defects in limb morphologyv.2 We previously reported (WBG 12(5): 82) that ceg-l maps to chromosome V just to the left of the cluster. We have now mapped ceg-l to the genetic map by PCR from single dead embryos homozygous for either the deficiency sDf30 or the deficiency sDf20 and find that it maps to the cluster of lethals near dpy-l l which lie under both deficiencies. Developmental Northern blots show that ceg-l encodes a moderately rare transcript that is present in late embryos and L1 larvae. Sequencing of genomic and cDNA clones reveal that the ceg-l gene has eight introns and encodes a 1.7kb message which is trans-spliced to SL1. We are now preparing to inject heat-shock and LacZ contructs. We are also collaborating with Ronald Plasterk to obtain a Tc1 insertion in ceg-l. Kingsley, D. M., Genes and Development 8: 133-146, 1994. 2 Storm, E. E., Huynh, T. V., Copland, N. G., Jenkins, N. A., Kingsley, D. M., and Lee, S. Nature 368: 639-643. 1994.

Po MD et al. (2012) Neuron "Releasing the inner inhibition for axon regeneration."

Po MD, Calarco JA, Zhen M

[Neuron, 2012]

The adult mammalian central nervous system exhibits restricted regenerative potential. Chen etal. (2011) and El Bejjani and Hammarlund (2012) used Caenorhabditis elegans to uncover intrinsic factors that inhibit regeneration of axotomized mature neurons, opening avenues for potential therapeutics.

Yandell MD et al. (1993) Worm Breeder's Gazette "A Worm Homolog of TGF-B"

Wood WB, Perry MD, Yandell MD

[Worm Breeder's Gazette, 1993]

TGF- -like proteins are important players in both vertebrate and invertebrate development. We have used degenerate PCR to look for C. elegans TGF- homologs. Following the approach of Wharton, et al. (PNAS 88: 92149218, 1991), we took advantage of the extensive sequence information available to group the TGF- -like proteins into subfamilies and thereby minimize primer degeneracy by making sets of primers specific to each subfamily. To date, using genomic DNA as template, we have recovered one homolog and have tentatively named the gene ceg-1 (for C. elegans growth factor 1). Sequencing of the PCR product and prediction of the processed mRNA and encoded amino acid sequence revealed a high degree of similarity to the bone morphogenetic protein (BMP) subfamily of TGF- -like proteins (see below). The indicated intron positions were based on predicted splice donor and acceptor sites with excellent match to the C. elegans consensus sequences, flanking regions with no significant TGF- similarity. Hybridization of the PCR product to the YAC grid located this sequence on three overlapping YACs just to the left of the cluster on chromosome V. This position was confirmed and refined by using PCR to map the gene to a single cosmid. Hybridization of labeled PCR product to Northern blots of RNA from different stages detected a transcript of about 2 kb, in the expected size range for a TGF- -like mRNA, which was abundant in embryos and less abundant in adults. We are continuing to characterize ceg-1 molecularly. We are also using PCR to test for its presence in embryos homozygous for appropriate deficiencies in order to map it relative to the several lethals in this region, which could be candidates for future transformation rescue experiments. It seems likely that there may be more than one TGF- homolog in C elegans, and we are continuing to search for others.

Sallee MD et al. (2015) Cell Cycle "Flipping the switch: regulating MTOC location."

Feldman JL, Sallee MD

[Cell Cycle, 2015]

Walker MD et al. (2021) Genetics "WormPaths: Caenorhabditis elegans metabolic pathway annotation and visualization."

Giese GE, Walhout AJM, Zhang H, Na H, Yilmaz LS, Li X, Bhattacharya S, Walker MD, Mirza Z, Diot C, Horowitz BB, Garcia-Gonzalez AP, Leland T, Nanda S, Zhang J, Ponomarova O, Lee YU, Holdorf AD

[Genetics, 2021]

In our group, we aim to understand metabolism in the nematode Caenorhabditis elegans and its relationships with gene expression, physiology and the response to therapeutic drugs. Visualization of the metabolic pathways that comprise the metabolic network is extremely useful for interpreting a wide variety of experiments. Detailed annotated metabolic pathway maps for C. elegans is mostly limited to pan-organismal maps, many with incomplete or inaccurate pathway and enzyme annotations. Here we present WormPaths, which is composed of two parts: 1) the careful manual annotation of metabolic genes into pathways, categories and levels, and 2) 62 pathway maps that include metabolites, metabolite structures, genes, reactions, and pathway connections between maps. These maps are available on the WormFlux website. We show that WormPaths provides easy-to-navigate maps and that the different levels in WormPaths can be used for metabolic pathway enrichment analysis of transcriptomic data. In the future we envision further developing these maps to be more interactive, with an analogy of road maps that are available on mobile devices.

Meneghini MD et al. (1997) International C. elegans Meeting "Morphogenesis defects in or34 embryos"

Thorpe CJ, Bowerman BA, Meneghini MD

[International C. elegans Meeting, 1997]

We have identified a maternal effect embryonic lethal mutation called or34. or34 embryos have a highly penetrant morphogenesis defect. These embryos produce mishapen clumps of well differentiated tissues and fail to elongate. One specific defect of or34 mutant embryos is the improper orientation of the mitotic spindle apparatus in an 8-cell stage blastomere called ABar. The ABar spindle orientation is of particular interest to us because a similar defect is caused by mutations in the mom genes which encode Wnt family signal transduction components. While the most obvious defect in the mom mutants is their failure to induce endoderm, this induction appears to occur normally in or34 mutant embryos. We are interested in the possibility that or34 is a weak allele of a new mom gene or defines a new gene required for a subset of processes under control of the Wnt pathway in the early embryo. or34 maps to the right arm of chromosome I. Complementation tests show that or34 is not allelic to mom-4 or mom-5 which also map to the right arm of chromosome I. We are currently pursuing a more detailed genetic and phenotypic analysis of or34.

Jacobson MD et al. (1994) Curr Biol "Apoptosis. Breaking the ICE."

Jacobson MD, Evan GI

[Curr Biol, 1994]

Perry MD et al. (1995) International C. elegans Meeting "ENIGMA: DECIPHERING MASCULINE MESSAGES"

Extavour C, Wilson E, Perry MD, Rajwans N

[International C. elegans Meeting, 1995]

The her-1 gene on LG V is required for normal male development in X0 animals. Our hypothesis, based on data from genetic and molecular experiments, suggests one of the X0-specific products of this locus is secreted and functions cell-non-autonomously to specify male fates. However, this model does not encompass the locus smaller, more abundant, male-specific transcript comprised of the two P2 promoter-proximal exons. We are investigating whether this other her-1 transcript has a biological function in C. elegans. Phenotypically, mutations that abrogate exclusively the larger her-1 transcript appear indistinguishable from a null allele disrupting both transcripts. In contrast to the masculinizing mRNA, the conceptual translation product from the smaller transcript lacks an obvious secretion signal. To establish if the SL1-trans-spliced polyadenylated RNA is translated we are using anti-her-1 antisera to detect the predicted 10 kDa protein. In parallel, we will assay epitope-tagged variants of this putative protein in transgenic worms. Finally, demonstrating translation of the ORF in vivo will make it feasible to screen nematode cDNA expression libraries for potential interacting proteins.