The long-term objective of this proposal is to gain insight into specific biochemical functions of the fragile X mental retardation protein (FMRP) through a molecular genetics approach that utilizes the fruit fly Drosophila melanogaster as a model system. The amenability of Drosophila to transgenic studies allows for in vitro engineered mutant alleles of dfmr1 to be introduced into flies lacking an endogenous wild-type allele. Recently, Tudor/Agenet domains have been defined in FMRPs, and these domains are related to ones known to modulate chromatin structure. We will generate alleles designed to disrupt the function of these domains and examine the effect of the mutations on neural development, behavior, and chromatin structure. These studies will help define what roles the Tudor/Agenet domains have for dFMR1 function. To find a role in chromatin regulation for Drosophila FMR1 will be a novel and significant function for the protein, and the results from this study will likely be applicable all members of the FMR1 gene family. Fragile X mental retardation is caused by loss-of-function of the FMR1 gene and is the most prevalent inherited form of mental retardation resulting from a single gene defect. The frequency of this disorder (about every 6000 births) and its global distribution make fragile X mental retardation one of the most prominent human genetic disorders. Understanding the mechanisms by which fragile X protein exerts its functions will provide insight into basic mechanisms of how synaptic plasticity (memory) is modulated and may open further avenues for pharmacological treatment of this significant human disorder. ? ? ?
| Banerjee, Paromita; Schoenfeld, Brian P; Bell, Aaron J et al. (2010) Short- and long-term memory are modulated by multiple isoforms of the fragile X mental retardation protein. J Neurosci 30:6782-92 |
| Banerjee, Paromita; Nayar, Shweta; Hebbar, Sarita et al. (2007) Substitution of critical isoleucines in the KH domains of Drosophila fragile X protein results in partial loss-of-function phenotypes. Genetics 175:1241-50 |
