Loss of Fragile X Mental Retardation protein (FMRP) causes Fragile X mental retardation syndrome. The molecular role of FMRP is not known. We established a model to study Fragile X using the Drosophila Fragile X protein homologue, dFMRl. We have shown that dFMR1 associates in a ribonucleoprotein complex and colocalizes with oo18 RNA binding (Orb) protein. dFMRl represses translation of Orb and Orb regulated mRNAs required for oogenesis. Orb is a Cytoplasmic Poly-adenylation Element Binding (CPEB) homologue. CPEBs are ribonucleoprotein complex components that regulate mRNA translation. Both CPEB and FMRP localize in vertebrate neurons. We hypothesize that dFMRl masks Orb's function as a regulator of cytoplasmic poly-adenylation induced translation of specific mRNAs during oogenesis. A CPEB/FMRP complex may act similarly in neurons. Loss of FMRP repression of CPEB may underlie Fragile X syndrome. I will investigate our hypothesis as follows:
Specific Aim I : To determine how dFMRl represses Orb regulated translation of target mRNAs.
Specific Aim II : To determine if the dFMR1/ORB interaction is direct and specific.
Specific Aim III : To identify and functionally analyze other members of the Orb/dFMR1 complex. ? ?
