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, presenilin 1 (PS1) and presenilin 2 (PS2). Mutations in PS1 are linked to about 25% of cases of early-onset familial Alzheimer's disease. PS1, which is endoproteolytically processed in vivo, is a multipass transmembrane protein and is a functional homologue of SEL-12, a Caenorhabditis elegans protein that facilitates signalling mediated by the Notch/LIN-12 family of receptors. 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 Dll1 (delta-like gene 1), 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 Dll1, which are essential for somite segmentation and maintenance of somite borders.
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