Department of Cell Biology
Harvard Medical School
LHRRB Building, Room 410
240 Longwood Ave.
Boston, MA 02115
Lab Members: 10 postdoctoral fellows
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 signaling pathways. Using Drosophila as our main experimental system we have been dissecting and studying a developmentally fundamental and evolutionary conserved cell signaling mechanism, the Notch pathway. Mutations in Notch signaling result in the abnormal development of a very broad spectrum of structures in Drosophila while malfunction of Notch signaling in humans has been associated with specific pathologies including neoplastic conditions. The central element of this signaling 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 signaling 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 signaling, 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 signaling 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 a the Alagille syndrome, a pleiotropic disease possibly associated with vessel abnormalities.
During the past few years, we have developed transgenic mouse models that allow us to address some of the above questions and have been focusing our attention to the mammary epithelium. We have been thus successful both in inducing tumors in the mammary gland under defined molecular and genetic conditions such that allow us to molecularly dissect the pathogenic process. Moreover we have been successful in affecting the oncogenic conditions by modulating Notch activity in specific mammary tumors. Finally, we have been studying the influence Notch signals have on the morphogenesis and stem cell differentiation of the intestinal epithelium. These are avenues of research that are substantially growing in our laboratory.
Fre, S., Huyghe, M., Mourikis, P., Robine, S., Louvard, D., and Artavanis-Tsakonas, S., (2005). Notch signals control the fate of immature progenitor cells in the intestine. Nature 435: 964-968.
Mukherjee, A., Veraksa, A., Bauer, A., Rosse, C., Camonis, J., and Artavanis-Tsakonas, S., (2005). Regulation of Notch signalling by non-visual beta-arrestin. Nat Cell Biol. (12):1191-201.
Louvi, A., Arboleda-Velasquez, J., Artavanis-Tsakonas, S., (2006). CADASIL: a critical look at a Notch disease. Dev. Neurosci. 28(1-2):5-12.