DROSOPHILA MELAGONASTER AS A MODEL SYSTEM TO INVESTIGATE THE GENETIC AND MOLECULAR FUNCTIONS OF TRANSCRIPTION FACTORS INVOLVED IN CONGENITAL HEART DISEASES

Congenital heart diseases are the cause of death for about 1 out of 100 live-born babies and 1 in 10 still-borns and are a source of high medical expenses due to complex surgical interventions. Our research proposes the use of the fruit fly (Drosophila melanogaster) as a model system for the study of the molecular functions of genes involved in the outset of congenital heart diseases. The Drosophila genome has been entirely sequenced and it is twenty times smaller in number of bases than the human one. About 75% of the genes involved in human genetic disorders have at least one homologue in the fly genome. Considering its speed of development, its inexpensiveness and the possibility to undertake genetic manipulations, this organism can well be used as a tool to understand the molecular functions of genes involved in human diseases, as demonstrated by recent studies. The genes that we will investigate encode proteins (transcription factors) that regulate expression of downstream target genes directly involved in the morphogenesis and physiology of the heart. Drosophila possesses a cardiac tube subdivided in an anterior portion named aorta and a posterior one named heart, able to autonomously pump. We identified the regulatory sequences of three genes expressed specifically in the heart and regulated by Hox genes, key genes in the development of all animals. We plan to use these sequences to identify the transcription factors responsible for their cardiac-specific regulation. These studies may provide useful paradigms for unraveling the developmental mechanisms of human heart development. Finally, through their overexpression in fly embryos, we have developed a system to study in vivo the regulatory properties of three human transcription factors responsible for congenital heart diseases (GATA4, NKX2.5 and TBX5), to understand the functions affected in individuals carrying mutations in these transcription factors that lead to congenital heart diseases.