Martinez-Arias Lab
Department of Genetics, University of Cambridge
Silvia Muñoz Descalzo
sm684@cam.ac.ukDepartment of Genetics,
Downing Street, Cambridge
CB2 3EH,England
Telephone: +44 1223 766586
Fax: +44 1223 333992
The Notch genes encode members of a family of single transmembrane receptors that mediate short-range signalling events. Notch acts as a membrane tethered transcription factor. Upon binding its ligands (Delta and Serrate/Jagged), which are also transmembrane proteins, Notch undergoes a series of cleavages that release of intra-cellular domain (NICD) that translocates to the nucleus where it regulates gene expression by acting as a co-activator of the transcription factor Suppressor of Hairless (Su(H)). The biochemical mechanisms that liberate the transcriptional activity of Notch are well established and recent studies, particularly in Drosophila suggest that endocytosis and traffic of Notch are required for the generation and activity of NICD.
There is evidence that Notch can signal independently of this transcriptional activity. This Su(H) independent activity targets Armadillo, that is the Drosophila homologue of β-catenin, and the effector of Wnt signalling. A function for Notch in the modulation of this signalling pathway has been analyzed over the years in AMA's lab. These analyses have provided a basis to interpret reports of interactions that exist in the literature and a framework to probe into the mechanism. Recently, AMA's lab has shown that the activity of Notch that modulates the activity of Armadillo is tightly associated with the ligand independent traffic of Notch. Since I joined AMA's lab I have been characterizing the nature of this activity of Notch.
Thus, it appears that the traffic of the Notch receptor is closely associated with its function and that understanding its mechanisms and modes of signalling will require a close analysis of its trafficking through the cell. The main objectives of my work are to find the mechanism of the ligand independent activity of Notch, as well as its relationship to the ligand dependent function. Specifically I would like to ask what are the spatial organization, kinetics and relationships of the ligand dependent and ligand independent traffic of Notch. I shall pursue these questions in the Drosophila wing imaginal discs because of the accessibility of this tissue to experimental manipulation and the genetic tools available which allow a detailed analysis of any process at a molecular and cellular level.
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