GENERATION OF MUTANT MOUSE MODELS FOR THE STUDY OF AETIOPATHOGENESIS OF HUMAN WILLIAMS-BEUREN SYNDROME

Williams-Beuren syndrome WBS) is a polysymptomatic complex including cardio-vascular defects, elfin-like face, infantile hypercalcemia, cerebral dysplasias and a peculiar cognitive-behavioural profile, characterized by impaired visuo-motor coordination, relatively good auditory rote memory, relatively spared morpho-syntactic linguistic skills and impaired semantic abilities, absence of any shyness by affected children toward unknown adults. This syndrome affects about 1 out of 20, 000 people and it is very often associated to the deletion of a small region of chromosome 7, where about 20 genes have been mapped. Whereas there is agreement that cardio-vascular defects are mainly consequence of the deletion of a particular gene in this region, the elastin one, genesis of other symptoms, and in particular of neurological symptoms, is still obscure. Our intention is to cast light on this problem, by generating murine models of this syndrome and analyzing cortical development and behavioural traits of these mutants. We will selectively inactivate in the embryonic brain the murine homolog of one of the genes mapping in the cromosomal region deleted in WBS patients, Fzd9, whose specific expression in the embryonal cortex strongly suggests its key involvement in the proper development of this structure. In parallel, by taking advantage of a powerful, recently set-up technology, we will generate mouse mutants, bearing small, different and partially overlapping deletions in the region of their chromosome 5 homologous to that of the human chromosome 7 reported above. These mice will be valuable tools for reconstructing contribution of other genes of this region to normal neurological development and for understanding how deletion of these genes can contribute to the development of neurological traits of WBS.