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 Alzhe imer'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 signali ng through an activated version of the Notch receptor LIN-12. To investigat e 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 g enetic strategy to isolate deletion alleles of both loci. Animals bearing b oth hop-1 and sel-12 deletions displayed new phenotypes not observed in ani mals bearing either single deletion. These new phenotypes-germ-line prolife ration defects, maternal-effect embryonic lethality, and somatic gonad defe cts-resemble those resulting from a reduction in signaling through the C. e legans Notch receptors GLP-1 and LIN-12. Thus SEL-12 and HOP-1 appear to fu nction redundantly in promoting Notch-pathway signaling. Phenotypic analyse s of hop-1 and sel-12 single and double mutant animals suggest that sel-12 provides more presenilin function than does hop-1.