Fine-Scale Regulation of Notch Signalling Dynamics: in the Context of Vertebrate Segmentation Clock

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During development, cells divide and take on different fates to make tissues that grow and become patterned to form body organs in a highly co-ordinated fashion. Loss of this co-ordination leads to birth defects and/or cancer. This co-ordination relies on highly sophisticated and tightly regulated communication between cells in the developing embryo. This communication is facilitated by molecular signalling pathways whereby cells send molecular signals to one another and respond accordingly. We will investigate this focussing on development of one organ; the segmented skeleton, a feature of all vertebrate species. One of the major signalling pathways that regulates cell division and directs cells to take on specific fates which ultimately leads to correct tissue formation throughout development is the Notch signalling pathway which we and others have shown is essential for segmentation. When the pathway is activated, a fragment of NOTCH protein, called "NICD" is released and switches on other target genes. Subsequently, NICD is destroyed. When this "off" switch is faulty the pathway is activated too strongly which causes numerous cancers. The details of how this "off" switch is controlled is not known. We aim to determine how the level of NICD is controlled, and how this co-ordinates skeletal development. This will be very informative to disease contexts where the "off "switch is faulty.