Approximately 10% of cases of Alzheimer's disease are familial and associated with autosomal dominant inheritance of mutations in genes encoding the amyloid precursor protein¹, presenilin 1 (PS1)² and presenilin 2 (PS2)^3,4. Mutations in PS1 are linked to about 25% of cases of early-onset familial Alzheimer's disease⁵. PS1, which is endoproteolytically processed in vivo⁶, is a multipass transmembrane protein and is a functional homologue of SEL-12 (ref. 7), a Caenorhabditis elegans protein that facilitates signalling mediated by the Notch/LIN-12 family of receptors^8,9. To examine potential roles for PS1 in facilitating Notch-mediated signalling during mammalian embryogenesis, we generated mice with targeted disruptions of PS1 alleles (PS1^–/– mice). PS1^–/–embryos exhibited abnormal patterning of the axial skeleton and spinal ganglia, phenotypes traced to defects in somite segmentation and differentiation. Moreover, expression of mRNA encoding Notch 1 and DII 1 (delta-like gene I)¹⁰, a vertebrate Notch ligand, is markedly reduced in the presomitic mesoderm of PS1^–/– embryos compared to controls. Hence, PS1 is required for the spatiotemporal expression of Notch 1 and Dll 1, which are essential for somite segmentation and maintenance of somite borders^11–13.