Nature 387, 288 - 292 (15 May 1997); doi:10.1038/387288a0

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

Philip C. Wong^*†£, Hui Zheng^‡£, Hua Chen^*†, Mark W. Becher^*†, Dalip J. S. Sirinathsinghji^§, Myrna E. Trumbauer^‡, Howard Y. Chen^‡, Donald L. Price^*†¶, Lex H. T. Van der Ploeg^‡ & Sangram S. Sisodia^*†

Departments of ^* Pathology, Neuroscience and ^¶ Neurology, and ^† the Neuropathology Laboratory, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
^‡ Department of Genetics and Molecular Biology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
^§ Merck Sharp and Dohme Research Laboratories, Neuroscience Research Center, Terlings Park, Eastwick Road, Essex CM20 2QR, UK
^£ These authors contributed equally to this work.

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 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 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.

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