The FMR gene family consists of fragile X mental retardation 1 (FMR1) and the closely related FXR1 and FXR2 genes. The FMR1 product (FMRP) is an RNA-binding, polyribosome-associated protein that regulates translation. Loss of FMRP function causes fragile X syndrome (FXS), the most common heritable form of mental retardation, and autism spectrum disorder. Neurological symptoms include hyperactivity, childhood epilepsy and cognitive dysfunction, and non-neurological symptoms include connective tissue abnormalities, ovarian failure in females, and enlarged testes in males. It has been proposed that FXR1 and FXR2 also have some function in FXS, but the relationship of these genes to neurological disease is not known.

In Drosophila, there is a single FMR1 gene (dFMR1) that has close homology to the human FMR genes. Elimination of dFMR1 from the fly results in phenotypes reminiscent of those observed in humans. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) have altered synaptic structures that appear immature and are associated with inappropriate synaptic connectivity. In Drosophila, the protein encoded by dFMR1 suppresses neuronal protein synthesis and its loss results in the elevated expression of protein in the brain. Mutant flies also experience non-neuronal symptoms, and fecundity is reduced in mutant male flies. This system provides a tractable model to begin to elucidate the independent roles of the three human FMR genes.

In this study, the authors introduce all three human FMR genes (FMR1, FXR1 and FXR2) into a well-characterized Drosophila FXS disease model. Only the FMR1 gene rescues neurological dysfunction. Flies expressing human FMR1 exhibit normal levels of protein in the brain, establish proper neuronal connections in the central brain circadian clock circuit, and exhibit complete synaptic differentiation. FMRP has a unique neuronal function that is independent of either FXR1P or FXR2P, and it cannot be replaced by FXR1P or FXR2P. In the fly testes, all three human genes are independently able to restore male fecundity and rescue defects in spermatogenesis. Thus, the requirement for FMR genes is different in neuronal versus reproductive tissues (or possibly all non-neuronal tissues), and this probably reflects tissue-specific functions of their resulting gene products.

This study demonstrates total functional conservation of the FMR family of genes, including FMR1, validating Drosophila as a relevant disease model for understanding this form of retardation and autism. The tissue-specific influence of FMRP on neurons indicates that its function is necessary for proper neurological function and that it is non-redundant with its gene family members. This Drosophila model will probably prove valuable for future structure-function analyses of human FMRP to define how the protein is regulated and which domains are important for its function in vivo.

2010