Dominant mutations in the human presenilin genes PS1 and PS2 cause early-onset Alzheimer's disease via an unknown mechanism1. In addition, loss-of-function mutations in C. elegans and mammalian presenilin genes have revealed that one aspect of their wild-type function is to facilitate Notch pathway signaling during development2-4. C. elegans has three presenilin genes,
sel-122,
hop-15 and
spe-46. Of these,
sel-122 and
hop-15 have been implicated in
lin-12/glp-1 signaling.
sel-12(lf) mutations suppress
lin-12(gf) phenotypes and enhance
lin-12(lf)/glp-1(lf) phenotypes. Yet, with the possible exception of an egg-laying defect, they display no Lin-12/Glp-1 phenotypes in a non-sensitized background2. Results from RNAi experiments suggest that
hop-1 may act redundantly with
sel-12 to promote
lin-12/glp-1 signaling5. However, we find that our previously described
hop-1 deletion mutant,
nr20037, has essentially no phenotype on its own and fails to suppress
lin-12(
n950gf). To further address the issue of whether
sel-12 and
hop-1 have redundant functions, we sought to generate a
hop-1;
sel-12 double mutant. As a first step toward this goal, a PCR-based screening technique (see Clover et al. abstract) was used to identify the deletion allele
sel-12(
nr2011). The
nr2011 deletion removes exons 3-6 and is predicted to encode a severely truncated gene product. Like previously described
sel-12(lf) mutations2,
sel-12(
nr2011) causes a highly penetrant egg-laying defect and suppresses
lin-12(
n950gf).
hop-1(
nr2003);
sel-12(
nr2011) double mutants exhibit new phenotypes not seen in either single mutant, providing genetic support for the hypothesis that the two genes share some functions. Furthermore, the phenotypes observed, namely somatic gonad defects, germline proliferation defects and maternal-effect embryonic lethality, resemble those displayed by
lin-12(lf) or
glp-1(lf) mutants8-10. Interestingly, which of these phenotypes is seen varies with maternal genotype:
hop-1;
sel-12 animals segregating from
hop-1/+;
sel-12 mothers exhibit stronger defects than do
hop-1;
sel-12 animals segregating frxom
hop-1;
sel-12/+ mothers. Together with the
hop-1 and
sel-12 single mutant phenotypic data, this result suggest that
sel-12 supplies most
lin-12/glp-1- related presenilin function in C. elegans, while
hop-1 plays a supporting role. 1Hardy, J. (1997) TINS 20:154-159. 2Levitan, D. and Greenwald, I. (1995) Nature 377:351-354. 3Shen, J. et al. (1997) Cell 890:629-639. 4Wong, P.C. et al. (1997) Nature 387:288-292. 5Li, X. and Greenwald, I. (1997) Proc. Natl. Acad. Sci. USA 94:12204-12209. 6L'Hernault, S.W. and Arduango, P.M. (1992) J. Cell Biol. 119:55-68. 7Westlund, B. et al. 1997 C. elegans International Worm Meeting abstract 171. 8Greenwald, I. et al. (1983) Cell 34:435-444. 9Austin, J. and Kimble, J. (1987) Cell 51:589-599. 10Priess, J. et al. (1987) Cell 51:601-611.