Fragile X syndrome is a common (1 in 6000 births) form of inherited mental retardation that arises from mutation of the FMR1 gene. The fragile X protein (FMRP) is an RNA binding protein that plays a major role in behavioral and synaptic plasticity by regulating local protein synthesis in response to neurotransmitter stimulation. The majority of FMRP analyses come from in vitro biochemical assays and cell culture models and, as a result, little is known about the importance of the individual domains in an intact animal model. The development of the Drosophila model for fragile X syndrome with phenotypes similar to those observed in mice and humans lacking FMR1, underscores the relevance of this model for FMRP function and provides a means to uncover novel functions of FMRP.
A molecular genetics approach was utilized to analyze functions of individual domains within dFMR1. These studies provide evidence that multiple domains present in FMRP are critical for its function, perhaps working both in concert and through separate molecular pathways. The C-terminal region of Drosophila fragile X protein has a domain enriched in glutamine/asparagine (Q/N) residues. Q/N domains are known modules for protein-protein interaction. The Q/N domain deletion alleles of dfmr1 showed that it is essential for regulating behavior and memory phenotypes, presumably through mediating dFMR1 assembly into ribonucleoprotein (RNP) complexes that regulate translation. These alleles will be vital for identification of RNP complexes that contain the dFMR1 Q/N(+) protein. Such RNPs may harbor proteins and RNAs that are critical components for establishment and consolidation of behavioral memory. Analysis of flies expressing the dFMR1 ΔQ/N protein indicates that dFMR1 has a role in regulation of alternative splicing of its own and other target mRNAs, perhaps by helping to confer distinct RNA and/or protein binding profiles to dFMR1. Identification of novel functions for FMRP may uncover new avenues for therapeutic interventions.