PREP TALE PROTEINS IN DEVELOPMENT AND IN HUMAN PATHOLOGY

Down Syndrome is caused by the presence of an extra copy of chromosome 21. Its phenotype, therefore, must be due to the overexpression not of a single gene, but of several genes, possibly at least fifty. It is possible that some of these are more important than others because their action depends on an accurate balance between their expression and that of other genes, mapping on other cromosomes. This is the case of Prep1 (chromosome 21), which functions in couple with Pbx proteins which map on other chromosomes in embryo development and in the adult, regulating growth and differentiation of several types of cells. This project aims at studying at various levels the molecular mechanisms and the actual physiological functions of the Prep1 gene and protein, and of its homolog (Prep2) which might compensate for its absence (in laboratory k.o.). The effect of Prep1 overexpression will be studied both in cell culture (molecular mechanisms) and in the mouse, targeting specifically one organ, thymus, important in our defense against infections and in the development of the immune system. Moreover, this study will be complemented by studies in simpler animals (Zebrafish) in which we have observed that Prep1 overexpression causes important defects in the skeleton and cranium, and in the develomment of the Central Nervous System. Finally, the physiological role of Prep1 (and Prep2) will be studied through the analysis (Prep1) and the generation (Prep2) of k.o. mice, and through crosses of these mice with others deficient in one of the Pbx genes, i.e. the physiological molecular partner of Prep. Also in this case we will exploit Zebrafish to study in detail (and rapidly) the effects of the absence of the Prep1 gene, since in this species there already exist mutants in this gene with phenotypes affecting the Central Nervous System.