Understanding the normal physiological functions of PS1 may shed light on the pathogenic mechanism of FAD-linked PS1 mutations. Identification of the PS1 homologue in C. elegans, sel-12, which facilitates signalling mediated by the Notch

PS1 is a major gene responsible for familial Alzheimer’s disease (FAD), and mutations in PS1 account for approximately 50% of early-onset FAD cases (Selkoe, 1998). Understanding the normal physiological functions of PS1 may shed light on the pathogenic mechanism of FAD-linked PS1 mutations. Identification of the PS1 homologue in C. elegans, sel-12, which facilitates signalling mediated by the Notch homologue LIN-12, provided the first evidence that PS1 interacts with the Notch signalling pathway (Levitan and Greenwald, 1995). The LIN-12/Notch family of receptors mediates cell-cell interactions that specify cell fate during development. SEL-12 affects LIN-12 activity by regulating its processing or trafficking (Levitan and Greenwald, 1998). PS1 shares functional homology with SEL-12, based on the finding that the wild-type human PS1 cDNA complements the sel-12 mutant phenotype (Baumeister et al., 1997; Levitan et al., 1996). However, PS1 containing FAD-linked mutations exhibited reduced ability to rescue sel-12 mutations, suggesting that mutant PS1 has reduced biological activity (Baumeister et al., 1997; Levitan et al., 1996). Recent identification of the Drosophila Presenilin (PS) provided further evidence for the interaction between PS1 and the Notch signalling pathway (Struhl and Greenwald, 1999; Ye et al., 1999). Fly mutants lacking both maternal and zygotic PS exhibit a neurogenic phenotype and are virtually indistinguishable from the Notch-null mutant, suggesting that PS function is required for normal Notch signalling in Drosophila (Struhl and Greenwald, 1999; Ye et al., 1999). PS is also required for the proteolytic cleavage of Notch to release its intracellular effector domain (ICD) (Struhl and Greenwald, 1999). The involvement of Presenilins in Notch processing is further supported by in vitro studies using truncated Notch1 and primary cell cultures derived from PS1−/− mice (De Strooper et al., 1999; Song et al., 1999). Levels of the ICD fragment were reduced in cultured PS1−/− neurons and fibroblasts, indicating that PS1 is important for the efficient proteolytic release of the ICD. PS1 bearing FAD-linked mutations exhibits reduced ability to rescue this Notch processing defect in cultured PS1−/− cells, suggesting that mutant PS1 has reduced activity in Notch processing (Song et al., 1999). To characterize the normal physiological role of PS1 in mice, we previously generated mice with a targeted germ-line disruption of the PS1 gene (Shen et al., 1997). Mutant mice homozygous for the resulting null allele exhibited similar defects in somitogenesis to those observed in Notch1-null mutant mice (Conlon et al., 1995; Swiatek et al., 1994), as well as severe malformation of the axial skeleton and cerebral hemorrhage (Shen et al., 1997; Wong et al., 1997). Furthermore, we showed that lack of PS1 results in a reduction 2593 Development 127, 2593-2606 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 DEV4389