Abstract FR:

The secreted molecules of the family Hedgehog (Hh) play a crucial part during the development at the vertebrate ones and the invertebrates. The way of Hh indication is implied in the appearance of many cancers at the man (cancers of the skin, brain of the prostate and digestive system). From the functional conservation of indication Hh enters the vertebrate ones and the drosophila, the latter remains a model privileged for the functional study of this way. During my thesis, I stuck to two aspects of Hh indication : The control of the diffusion and the movement of Hh since its producing cells, mechanisms of the transduction and the regulation of the Hh signalling the receiving cells. For that I studied the role of the lipidic modifications of Hh and their need in the activation of various target genes of the way. Hh is synthesized in the form of a precursor whose maturation is carried out before its secretion. The secreted factor corresponds to the Nfinal area of the precursor decorated with a cholesterol molecule out of C-terminal and with a palmitic molecule of acid out of N-terminal. I thus could show that the presence of cholesterol on Hh was necessary to its secretion and its diffusion beyond the cells which produce it, and that the presence of the palmitic acid was necessary for the potentiation of the Hh signal. The second part of my thesis is centered on the comprehension of the mechanisms of regulation of the Hh way and its various components. The Hh way consists of a complex of reception of the signal made up of the Patched receiver and of its Co-receiver smoothened (Smo), and of a complex of transduction of the signal whose principal components are: the kinésine costal-2 (Cos), kinase Fused (Fu), the factor of transcription ulna interruptus (Ci). I took part in the demonstration that the transmission of the Hh signal between its complex of reception and the complex of transduction of the signal are done by direct interaction between the co-receptor Smo and Cos. Thereafter, I was interested in the regulation of the stability of the proteins Smo and Cos. For that I carried out a clonal analysis in the disc imaginal of wing for various genes coding for kinases (such as PKA, GSK3) and of proteins of the complexes of ubiquitination (such ascertain components of complexes SCF). All these proteins are known to play a part in the stability and the regulation of the factor of transcription of the Hh way: Ci. The analysis of the loss of function clones for these various genes enabled me to select candidates implied in the stability of Cos. In order to better understand the regulation of the Hh way, I was interested in the characterization of a new gene (ripcurl: RPC) identified at the time of a mutagenesis of deregulation. The over-expression of RPC makes it possible to obtain similar phenotypes with losses of function of hh in the wing. I showed that RPC intervenes between the complex of reception and the cytoplasmic complex of transduction of the Hh signal. I also generated and characterized a mutant of RPC obtained by Re-mobilization of an element P in order to make a phenotypical study. Complementarily, I developed biochemical tools to allow myself to identify his partners.