ANALYSIS OF THE ROLE OF PITX2, THE GENE MUTATED IN RIEGER SYNDROME, IN VENTRICULAR MORPHOGENESIS: IMPLICATIONS FOR ADULT HEART FUNCTION

The incidence of congenital cardiovascular malformations in newborns and cardiac disease onset in adults is impressively high, therefore research projects aiming to understand the molecular pathways that regulate cardiac growth and function are very important. This research application is aiming to analyse the role in these processes of the homeobox gene Pitx2, whose mutations in humans are responsible for the Rieger syndrome. We have generated mice in which the Pitx2 gene is selectively deleted in the heart from early developmental stages (Pitx2 komyo mice). This results in malformed hearts, which have several morphogenetic defects such as the loss if the interatrial septum, and irregularly shaped ventricular chambers. These mice survive to adulthood, but they develop cardiac morphological and functional defects. In adult mice which have lost only one copy of the Pitx2 gene in the heart (heterozygous mice), only left ventricular dilation and dysfunction could be detected. We have analysed the cellular organization of the developing komyo hearts and we have noticed that they present a delay in cardiomyocyte maturation in the cells which have lost activity of the gene. Thus, we conclude that Pitx2 plays a role in cellular remodelling, which is the basis for global heart remodelling. The goal of this research project is to better understand the mechanism of action of Pitx2, and identify the molecular pathways through which Pitx2 regulates the cellular process of cardiac ventricular morphogenesis, which is crucial for proper adult cardiac function. This approach underscores a possible additional role of Pitx2 as susceptibility gene for cardiac disease, which will be explored. Our research will lead to understand the molecular basis of ventricular remodelling and will possibly genetically link Pitx2 to adult heart disease.