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Notch receptor cis-inhibition and developmental decisions: a live imaging analysis in Drosophila
Notch receptors mediate cell-cell signalling between juxtaposed cells in many contexts during development and tissue homeostasis in metazoans. Notch receptors often signal to control binary fate decisions between neighbouring cells as both receptors and ligands are transmembrane proteins present at the cell surface. Ligand–receptor trans-interaction, i.e. between neighbouring cells, results in Notch trans-activation. However, studies, for the most part in Drosophila, but also in vertebrates, have indicated that ligand–receptor interactions can also take place within the same cell. These cis-interactions reduce the ability of a cell to receive the signal from neighbouring cells by a process called ‘cis-inhibition’ of the
receptor by the ligand (1). The mechanism and functional significance of this process remains largely unexplored in the physiological context of the developping body.
Live imaging has recently emerged as a method of choice to quantitatively study the spatial and temporal regulation of signaling and developmental patterning processes. Our laboratory has extensive expertise in the live imaging of the developping adult fly. In particular, we have recently developped a number of geneticaly encoded fluorescent probes that serve as reporters for the localization and activity of Notch receptors in Drosophila. One such probe, NotchGFP, was used to monitor in real time the activity of Notch in living flies in the context of a well-defined binary fate decision (2).
The PhD project proposed here will aim at dissecting the molecular basis of the cis-inhibition process and its possible relevance in lateral inhibition. This project will address specific hypotheses about the role of compartmentalization and trafficking of Notch components in polarized epithelial cells in the cis-inhibition of Notch by its ligands. The relevance of cis-inhibition for Notch-mediated fate decision will be investigated in the context of the developmental patterning of adult sensory in the adult fly, a text-book example of lateral inhibition for which a role of cis-inhibition remains to be defined.
(1) D. del Alamo, H. Rouault and F. Schweisguth (2011) Review : Notch signalling: mechanism and functional significance of cis-inhibition. Current Biology, 21, R40-7.
(2) L. Couturier, N. Vodovar and F. Schweisguth (2012) Endoyctosis by Numb breaks Notch symmetry at cytokinesis. Nature Cell Biology, 14, 131-9
Cell fate decision, Notch, Drosophila, live imaging