With a $120,000 grant from FRAXA Research Foundation over 2 years, Dr. Thomas Dockendorff from the University of Tennessee and his colleagues were pioneers in using the power of fly genetics to understand the different functions of the fly version of the fragile X protein.
The genome of the fruit fly Drosophila melanogaster encodes a fragile X protein (FMRP) that is highly similar to human FMRP, and mutations in the Drosophila fragile X gene elicit phenotypes with significant parallels to those observed fragile X patients. These findings provided an opportunity to exploit the molecular genetics tools of fruit flies to uncover new mechanisms of FMRP function, and the biochemical pathways it regulates.
While much attention was justifiably given to the role of FMRP at synapses, there was a growing body of evidence that FMRP has functions in the nuclei of cells. One potential role for nuclear FMRP is to regulate chromatin structure, a process that can require the activity of RNA binding proteins and proteins that interact with methylated histones. Two Agenet domains are present in FMRP that are highly conserved between insects and vertebrates, indicating that they are important for FMRP function. This observation was of particular interest since the Agenet domain is a member of a protein family that binds both RNAs and methylated proteins.
Our goal for this FRAXA-funded project was to develop fly stocks with mutations that specifically disrupt the Agenet domains in Drosophila FMRP and then assess any neural development and behavioral phenotypes that arose. Defects in these phenotypes would strongly imply that the Agenet domains are essential for the full range of FMRP function. The fruit fly was an excellent model for studies of chromatin regulation, and an extensive array of mutant and transgenic fly stocks are available to help characterize the role of FMRP in this process.
The proposed studies of FMRP Agenet domains may uncover a new mechanism by which FMRP regulates gene expression and behavior. Important long-term goals were to identify the genes that are regulated in this manner and the mechanism(s) by which FMRP exerts these effects, with the hope that such efforts would point towards additional therapeutic strategies for fragile X syndrome.