MOLECULAR MECHANISM(S) UNDERLYING THE MRNA TURNOVER OF PITX2, A GENE INVOLVED IN THE AXENFELD-RIEGER SYNDROME PATHOGENESIS

Objective. This project aims to understand the molecular mechanism(s) by which Pitx2 mRNA turnover rate is modulated. Background/Rationale. Pitx2, one of the genes responsible for the human Axenfeld-Rieger syndrome (ARS), encodes a molecular region that exerts a crucial role during development of different organs touched in ARS, such as heart, pituitary and eyes. All proteins arise from RNAs, called mRNA, that encode the protein sequence. Interestingly, several mRNAs, such as Pitx2, display a high turnover rate caused by presence of instable Adenylate/uridylate-Rich Element (ARE) regions. In particular, it has been reported that Pitx2 mRNA stabilization is due to a reduced interaction of Pitx2 mRNA with the destabilizing ARE binding proteins (ARE-BPs) KSRP and TTP as well as to an increased interaction with a stabilizing ARE-BP, HuR. Description of the project. On the basis of the recent discovery that Pitx2 its-self can exert a dual role in modulating gene expression both at the transcriptional and at the post-transcriptional level, and in order to understand in details the combinatorial control of this, I will i) investigate the ability of KSRP interacting proteins in regulating the stability of Pitx2 mRNA; ii) generate animal models where either KSRP or HuR will be either deleted or overexpress in order to obtain a genetic proof of the biological relevance of these two ARE-BPs in regulating the Pitx2 mRNA turnover. Anticipated output. We have identified different KSRP interacting protein.