Presenilin 1 Is Required For Notch1 Dii1 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 protein(1), presenilin 1 (PS1)(2) and presenilin 2 (pS2)(3,4). Mutations in PSI are Linked to about 25% of cases of early-onset familial Alzheimer's disease(5). PS1, which is endoproteolytically processed in vivo(6), 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 1 potential roles for PS1 in facilitating Notch-mediated signalling during mammalian embryogenesis, we generated mice with targeted disruptions of PSI 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 Notch1 and Dill (delta-like gene 1)(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 Notch1 and Dll1, which are essential for somite segmentation and maintenance of somite borders(11-13).