The canonical Notch signal transduction pathway relies on proteolytic events that release the intracellular portion of the Notch receptor from its transmembrane domain. The final step in this ligand-triggered Notch activation is the intramembranous cleavage event carried out by the g secretase membrane complex. g secretase is composed of four subunits, Presenilin, APH-1, APH-2/Nicastrin, and PEN-2. The presenilin protein contains the catalytic core of the complex, while the other three subunits are thought to have critical roles in assembly and stability of the complex. In C. elegans two different presenilin genes,
sel-12 and
hop-1, function in the context of Notch signaling events and are redundant for most such events: single mutants are viable, fertile, and yield live progeny, while double mutants display Notch loss of function phenotypes (sterility, maternal-effect lethality, Pvl, and 2AC)1,2. Given that SEL-12 and HOP-1 share only 35.4% a.a. identity1, and have different expression patterns, we considered whether functional differences might exist between these presenilin proteins. Although much has been learned about the biochemical details of g secretase activity, little is known about its function over the course of development. Germ cell proliferation in the C. elegans gonad requires continuous GLP-1 Notch activation throughout larval and adult life3. We compared the need for
hop-1 and
sel-12 over the course of germline development. While
sel-12 and
hop-1 are redundant for mediating germline proliferation during larval development, we demonstrate that germline proliferation in the adult is mediated predominantly by
hop-1. In order to confirm that the required role of
hop-1 in the adult is to activate GLP-1, we used the hyperactive
glp-1(
ar202)4 allele that causes late-onset germ cell overproliferation (tumors), and we demonstrate that
hop-1(
ar179) is epistatic to
glp-1(
ar202) late tumor formation. Our analysis identifies the first unique role for
hop-1 in the context of Notch signaling, and we are now analyzing additional requirements for this role during adult germline proliferation. 1. Li and Greenwald '97; 2. Westlund et al. '99; 3. Austin and Kimble'87; 4. Pepper et al. '03.