Presenilin 1 is required for Notch 1 and Dll1 expression in the paraxial mesoderm

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 receptors8,9. 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 borders11–13.