Mental retardation (MR) is a major cause of serious handicap in children and young adults and an important medical and social issue affecting 1 to 1.5% of the population. The Fragile X syndrome (FRAXA or FXS) is the most frequent hereditary cause of MR affecting 1/4000 males and 1/7000 females. FMRP, the protein absent in Fragile X patients, is an RNA binding protein component of heterogeneous ribonucleoparticles (mRNP). It plays a role in several steps of mRNA metabolism that range from mRNA transport to t he regulation of translation of target mRNA (G-quartet, kissing complex). In neurons, FMRP would control locally the translation of neurospecific mRNAs that are essential for synaptic development and maturation. Although many studies have shed new light on FMRP's role, its exact cellular function remains elusive and it still not clearly understood how the absence of a single protein can lead to such drastic phenotypic traits in FXS patients. We believe that the precise function of FMRP strongly depends on RNA and proteins that interact with it, therefore I propose to characterize the mRNP complexes containing FMRP, at the level of mRNA and protein composition. First, I will compare the composition and dynamics of these complexes in wild type and Fmr 1 null mice brain using FPLC combined with sucrose gradient.
Then, using a novel approach, I will characterize novel mRNA recognition sequences or structures bound by FMRP starting from its already defined (putative) targets RNA. Finally, I will investigate the role of FMRP interacting proteins in the modulation of its interaction with mRNAs by in vitro and in vivo approaches. This project will be developed in Dr. Bardoni's laboratory but also in close collaboration with European laboratories as well as 2 laboratories in North America working in the field.
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