Reverse genetic analysis of Caenorhabditis elegans presenilins reveals redundant but unequal roles for sel-12 and hop-1 in Notch-pathway signaling.
Mutations in the human presenilin genes PS1 and PS2 cause early-onset Alzheimer's disease. Studies in Caenorhabditis elegans and in mice indicate that one function of presenilin genes is to facilitate Notch-pathway signaling. Notably, mutations in the C. elegans presenilin gene sel-12 reduce signaling through an activated version of the Notch receptor LIN-12. To investigate the function of a second C. elegans presenilin gene hop-1 and to examine possible genetic interactions between hop-1 and sel-12, we used a reverse genetic strategy to isolate deletion alleles of both loci. Animals bearing both hop-1 and sel-12 deletions displayed new phenotypes not observed in animals bearing either single deletion. These new phenotypes-germ-line proliferation defects, maternal-effect embryonic lethality, and somatic gonad defects-resemble those resulting from a reduction in signaling through the C. elegans Notch receptors GLP-1 and LIN-12. Thus SEL-12 and HOP-1 appear to function redundantly in promoting Notch-pathway signaling. Phenotypic analyses of hop-1 and sel-12 single and double mutant animals suggest that sel-12 provides more presenilin function than does hop-1.
Axys Pharmaceuticals, NemaPharm Group, 100 Kimball Way, South San Francisco, CA 94080, USA.
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Westlund
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Parry
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Clover
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Basson
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Johnson
D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins; D004625:Embryo, Nonmammalian / Q000502:physiology; D004627:Embryonic Induction; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D015801:Helminth Proteins / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D016296:Mutagenesis; D009153:Mutagens; D010641:Phenotype; D051880:Receptors, Notch; D015398:Signal Transduction / Q000502:physiology*; D014466:Ultraviolet Rays; D014844:Vulva / Q000002:abnormalities / Q000196:embryology
D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; C109040:Hop-1 protein, C elegans; C082460:Lin-12 protein, C elegans; D008565:Membrane Proteins; D009153:Mutagens; D051880:Receptors, Notch; C095907:SEL-12 protein, C elegans