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Analysis of the negative elements controlling Lunatic fringe cyclic expression in the presomitic mesodem

Objective

Somitogenesis has been shown to involve a molecular oscillator called the \"segmentation clock\", which acts in prismatic cells. This molecular clock controls the periodic expression of \"cyclic genes\", which are, so far, all related to the Notch pathway. In the mouse, the cyclic genes include downstream targets of Notch such as those encoding the transcription factors, Hes1 and Hes7 (hairy homologues), and lunatic fringe (Long) that encode aglycosyl transferees, which modulates Notch activity. Recently, distinct cist-acting regulatory elements have been described in the 2.3 kb region in the Lfngpromoter that are required for enhancing and repressing cyclic Long transcription. Analysis of this promoter revealed that the Notch signalling acts directly via CBF1/RBP-ÿK to activate Long expression, and this result is supported by other lines of evidence such as the disruption of Long expression in Notch pathway mutants. Lassies known about how Long is repressed, although this aspect of the control must also be essential for cycling. Therefore, I will focus my analysis on the conserved repressing element, also called box C, that appears crucial to prevent continued expression in PSM and thus to underlie the cyclic Long transcription In order to identify more precisely the negative regulatory elements required for periodic Long expression, we will test the activity in transgenic mice of muleteers of the box C (native and mutated) fused upstream of a non-cycling promoter constitutively active in the PSM. Foot printing of the box C will be a complementary approach towards identification of the transcription factors controlling the cyclic Long repression. We will also try to make cell line derived from prismatic mesoderm using transgenic mice harbouring the thermo labile SV40 Tag gene. Such a model will allow us to perform in vivo foot printing at different steps of the cycle without quantitative limitations.

Call for proposal

FP6-2002-MOBILITY-5
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Funding Scheme

EIF - Marie Curie actions-Intra-European Fellowships

Coordinator

CANCER RESEARCH UK
Address
Lincoln's Inn Field 61
London
United Kingdom