PRESENILIN-1 IS REQUIRED FOR NOTCH1 DII1 EXPRESSION IN THE PARAXIAL MESODERM

Approximately 10% of cases of Alzheimer's disease are familial and ass ociated with autosomal dominant inheritance of mutations in genes enco ding the amyloid precursor protein(1), presenilin 1 (PS1)(2) and prese nilin 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 endoprot eolytically processed in vivo(6), is a multipass transmembrane protein and is a functional homologue of SEL-12 (ref. 7), a Caenorhabditis el egans protein that facilitates signalling mediated by the Notch/LIN-12 family of receptors(8,9). To examine 1 potential roles for PS1 in fac ilitating Notch-mediated signalling during mammalian embryogenesis, we generated mice with targeted disruptions of PSI alleles (PS1(-/-) mic e). PS1(-/-) embryos exhibited abnormal patterning of the axial skelet on and spinal ganglia, phenotypes traced to defects in somite segmenta tion and differentiation. Moreover, expression of mRNA encoding Notch1 and Dill (delta-like gene 1)(10), a vertebrate Notch ligand, is marke dly 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 main tenance of somite borders(11-13).