Spyros Artavanis-Tsakonas Biology and Genetics of Development (2000-2012)


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Our research focuses on the study of mechanisms governing the development of multicellular organisms. We are particularly interested in understanding how an undifferentiated precursor cell responds to developmental signals and progresses to the next developmental state. Many human pathologies, importantly cancer, involve the inability of cells to properly respond to developmental signals.

Acquisition of specific cell fates during development depends on an intricate interplay of signalling pathways. Using Drosophila as our main experimental system we have been dissecting and studying a developmentally fundamental and evolutionary conserved cell signalling mechanism, the Notch pathway. Mutations in Notch signalling result in the abnormal development of a very broad spectrum of structures in Drosophila while malfunction of Notch signalling in humans has been associated with specific pathologies including neoplastic conditions. The central element of this signalling pathway is the Notch surface receptor. A signal through Notch does not seem to convey specific instructions to the cell but rather modulates the ability of a non terminally differentiated cell to receive and/or interpret developmental signals that result in differentiation, proliferation, or even apoptosis. The Notch pathway is thus a fundamental regulator of cell fates in development, which is functionally and structurally conserved from worms to humans.

Using genetic and molecular approaches we have been studying this signalling mechanism and identified various elements of the biochemical cascade defining the pathway. Delta and Serrate encode ligands for the Notch receptor. Suppressor of Hairless encodes a transcription factor which acts as a downstream effector of Notch signalling. Hairless encodes a negative regulator of Notch signaling which is thought to act through direct association with Suppressor of Hairless and Deltex is a cytoplasmic, positive effector of the pathway that associates with the intracellular domain of the receptor. Recent studies have implicated several additional genes in the modulation of Notch activity. Moreover, a series of proteolytic events appear to control the functional state of both receptor and ligands. Much of our work is concerned with the study of the relationships between the various Notch pathway elements and their biochemistry.

As our understanding of the biochemical activities of Notch increases so is our ability to design experiments aimed at modulating Notch pathway activity in vivo. Given its fundamental and general involvement in the acquisition of cell fates we believe that modulation of Notch may lead to manipulating of stem cells in a variety of tissues. This in turn may be helpful in approaching tissue repair and many dysplastic conditions in a new light. In addition, our increased understanding of the molecular biology of Notch signalling suggests specific therapeutic avenues for diseases directly associated with Notch function such as some forms of lyphoblastic leukemia, the CADASIL syndrome, a late onset disease associated with strokes and dementia, and the Alagille syndrome, a pleiotropic disease possibly associated with vessel abnormalities.

We are continuing our efforts to understand cell fate acquisition at a mechanistic level using the power of genetics in simple experimental model systems as our primary tool. A new study, related to our general interests has been recently initiated. Namely we have started genetic screens in Drosophila to identify genes that affect size at an organismal and/or organ level. The extraordinary conservation of fundamental mechanisms across species barriers indicates that the study of experimental systems such as Drosophila or C.elegans provides a powerful and unique tool in the study of human biology.

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