SEL-12 facilitates
lin-12 mediated signalling and is highly similar to two human presenilins (PS1 and PS2), multipass membrane proteins that have been implicated in the development of Alzheimer's disease (Levitan and Greenwald, 1995). SEL-12 is a bona fide presenilin, since human PS1 or PS2 can rescue the egg-laying defective phenotype of
sel-12 mutants (Levitan et al., 1996). The genetic interactions between
sel-12 and
lin-12 have suggested several possible models for the role of
sel-12 in
lin-12 -mediated signalling: (1) SEL-12 could be acting as a co-receptor with LIN-12, (2) SEL-12 could function as a downstream effector of LIN-12, or (3) SEL-12 could function in more general cellular processes such as receptor biogenesis or trafficking. The
sel-12;
lin-12(intra) double mutant suggests that
sel-12 does not function as a downstream effector of
lin-12. We had previously shown that reducing
sel-12 activity suppresses the gain-of-function phenotypes oflin-12(d) mutations, which are point mutations in the extracellular domain of the intact receptor that behave like constitutively activated receptors and that
sel-12 can function in the same cell as
lin-12 .
lin-12(intra) expresses just the intracellular domain of LIN-12, which behaves as a constitutively activated receptor (Struhl et al., 1993). We found that reducing
sel-12 activity does not suppress the gain-of-function phenotypes of
lin-12(intra), implying that
sel-12 does not act downstream of activated LIN-12. Other double mutant combinations suggest that
sel-12 may be involved in more general cellular processes. We have constructed double mutants between
sel-12 and hypomorphic mutations in genes encoding other cell signalling proteins. We have found at least one other receptor whose activity seems to be reduced by reducing
sel-12 activity. Since antibody staining of human presenilins suggests that they are localized in the ER and Golgi, we are looking at the effects of reducing
sel-12 activity on the localization of GFP tagged receptors to see if we can find direct evidence for a role in receptor localization or recycling.