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Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants

Nature volume 398, pages 525–529 (1999)Cite this article

Abstract

Presenilin proteins have been implicated both in developmental signalling by the cell-surface protein Notch and in the pathogenesis of Alzheimer's disease. Loss of presenilin function leads to Notch/lin-12-like mutant phenotypes in Caenorhabditis elegans1,2 and to reduced Notch1 expression in the mouse paraxial mesoderm3. In humans, presenilins that are associated with Alzheimer's disease stimulate overproduction of the neurotoxic 42-amino-acid β-amyloid derivative (Aβ42) of the amyloid-precursor protein APP4. Here we describe loss-of-function mutations in the Drosophila Presenilin gene that cause lethal Notch-like phenotypes such as maternal neurogenic effects during embryogenesis, loss of lateral inhibition within proneural cell clusters, and absence of wing margin formation. We show that presenilin is required for the normal proteolytic production of carboxy-terminal Notch fragments that are needed for receptor maturation and signalling, and that genetically it acts upstream of both the membrane-bound form and the activated nuclear form of Notch. Our findings provide evidence for the existence of distinct processing sites or modifications in the extracellular domain of Notch. They also link the role of presenilin in Notch signalling to its effect on amyloid production in Alzheimer's disease.

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Figure 1: Identification of Psn mutations by genomic DNA rescue experiments.
Figure 2: Notch-like phenotypes in Psn mutant imaginal wing discs.
Figure 3: Neural hyperplasia in Drosophila embryos lacking maternal presenilin protein.
Figure 4: Immunohistochemical analysis of the Notch protein distribution in Psn-mutant eye imaginal discs.
Figure 5: Western immunoblot analysis of Notch C-terminal fragments and Delta in Psn mutants.
Figure 6: Effects of truncated, constitutively activated forms of Notch on SOP determination in Psn mutant tissues.

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Acknowledgements

We thank V. V. Roussakova for technical assistance with genetic screening and Drosophila microinjection; F. Schweisguth, G. Struhl, S. Artavanis-Tsakonas, D. Pan and R. Finkelstein for fly stocks; and S. Artavanis-Tsakonas, G. M. Rubin, Y. N. Jan and T. A. Jongens for antibodies. This work was supported by the NIH, the Life and Health Insurance Medical Research Fund, and the Alzheimer's Association.

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  1. Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Yihong Ye, Nina Lukinova & Mark E. Fortini

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  1. Yihong Ye
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Correspondence to Mark E. Fortini.

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Ye, Y., Lukinova, N. & Fortini, M. Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature 398, 525–529 (1999). https://doi.org/10.1038/19096

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