|Defining Functional Domains of FMRP and Uncovering its Partners via Large Scale Mutagenesis in Drosophila
by Xinda Lin, 3/1/2005
FMRP is a widely expressed RNA-binding protein involved in RNA transport and translation. Intensive studies in the last decade have demonstrated that FMRP contains four RNA binding domains, but their actual functions are mostly untested.
Meanwhile, a dozen or so protein partners and hundreds of mRNA targets interacting with FMRP have been identified, but again their functions are poorly understood. It is important that the functional domains of FMRP and its interacting partners be identified and characterized in order to understand the pathogenesis of Fragile X.
In the last five years, a Drosophila Fragile X model has provided a number of novel insights into FMRP function. Previous work was primarily focused on making null mutations of the gene and then analyzing the phenotypes of mutants to infer the normal functions of FMRP.We have recently developed a simple, efficient scheme to screen for genes that suppress FMRP. Overexpression of FMRP is fatal to flies, but a suppressor generated through mutagenesis can produce viable progeny.We plan to exploit the mutagenesis approach to 1) define essential sections of the FMRP molecule, and 2) to uncover physiologically important partners of FMRP, taking full advantage of sophisticated Drosophila genetics, molecular tools and cellular assays. The results of this project will advance our understanding of FMRP’s role, elucidating the pathways in which FMRP is involved and the molecular pathogenesis when FMRP is absent in Fragile X. This understanding will ultimately be used for the development of a drug treatment for the disease.