MOLECULAR MECHANISMS UNDERYING THE FUNCTION OF PITX2, A GENE CENTRAL TO THE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL REGULATION EXERTED BY WNT SIGNALING

The Axenfeld-Rieger syndrome (ARS) is a severe genetic disease which develops before birth. It is mainly characterized by eyes, face, tooth abnormalities, and, less frequently but not less importantly, heart malformations and growth problems due to defects in an endocrine gland called pituitary. ARS eye problems ultimately produce glaucoma, a severe damage to the optic nerve that represent one of the most frequent causes of vision loss. One of the genes responsible for ARS is called Pitx2. The protein produced by this gene is a factor able to regulate the expression of other genes. We have thoroughly studied how the expression of the Pitx2 gene is regulated, i.e. how the Pitx2 protein is produced. We have discovered that a cellular way to transmit signals, which is driven by the molecule Wnt, is one of the main Pitx2 regulators. Wnt, through other molecules, regulates Pitx2 expression that, in turn, regulates the expression of genes able to modulate cell proliferation. Recently, we discovered that Wnt regulates the life span of Pitx2 gene first product which is called Pitx2 messanger RNA, and other genes messanger RNAs. In order to understand how the ARS tissue damage takes place, we want to: 1. study in detail the genes that Pitx2 regulates and discover more genes regulated by Wnt/Ptx2; 2. investigate the molecules that cooperate with Pitx2 in exerting its crucial functions; 3. investigate in an animal model the Pitx2 gene regions responsible for the regulation of the life span of the messanger RNA. Even if the treatment of a complex disease that begins before birth and affects different organs is a very difficult task to pursue, we believe that the most useful way to face a disease is to know in detail the molecular mechanisms underlying the disease itself.