U Notch (N) is an important signaling protein that is known to be critical for embryonic development in most animals. Part of its essential role is to influence cell-fate decisions and to establish the proper number of progenitor neurons in the developing nervous systems of flies and humans. Our lab became fascinated with Notch after intriguing twin discoveries: (1) Notch is processed by a gamma-secretase complex containing Presenilin (Psn) into a signaling molecule that can enter the nucleus, and (2) mutations in human Psn correlate with the absolute development of some familial forms of Alzheimer's disease.
We have tested the requirement of Notch in adult fruit flies, Drosophila melanogaster, with a fully differentiated nervous system. This is possible because of the powerful molecular and genetic tools to compromise the Notch protein after development is complete using conditional alleles, inducible dominant-negative transgenes, or inducible RNAi molecules. We have shown that adult flies without functional Notch have a dramatically reduced lifespan, show impairments in locomotion with age, and display defects in long-term memory. The last phenotype is notably compelling because Notch-compromised adult flies display short-term memories that are indistinguishable from controls.
Currently we are using these Notch phenotypes to genetically map the regions of the fly brain necessary for long-term memory by selectively silencing Notch in defined subregions of the central nervous system.
Drosophila is an ideal model system for these investigations for two reasons. First, the molecular pathways contributing to Drosophila development and aging can be dissected using powerful genetic tools to assay the important functional genes. Second, many of these critical pathways are conserved through evolution from insects to vertebrates, and Drosophila has made substantial contributions to our current understanding of signaling pathways and disease pathologies in humans. Thus, we propose to investigate the hypothesis that the major role of Notch signaling in the adult nervous system is to contribute to plastic functions that include memory, and that we can use Drosophila to model important aspects of Alzheimer's disease.