Characterization of dFMR1, a Drosophila melanogaster homolog of the fragile X mental retardation protein

Fragile X syndrome is the most common inherited form of mental retardation. It is caused by loss of FMR1 gene activity due to either lack of expressio n or expression of a mutant form of the protein. In mammals, FMR1 is a memb er of a small protein family that consists of FMR1, FXR1, and FXR2. All thr ee members bind RNA and contain sequence motifs that are commonly found in RNA-binding proteins, including two KH domains and an RGG box. The FMR1/PXR proteins also contain a 60S ribosomal subunit interaction domain and a pro tein-protein interaction domain which mediates homomer and heteromer format ion with each family member. Nevertheless, the specific molecular functions of FMR1/FXR proteins are unknown. Here we report the cloning and character ization of a Drosophila melanogaster homolog of the mammalian PMR1/PXR gene family. This first invertebrate homolog, termed dfmr1, has a high degree o f amino acid sequence identity/similarity with the defined functional domai ns of the FMR1/FXR proteins. The dfmr1 product binds RNA and is similar in subcellular localization and embryonic expression pattern to the mammalian FMR1/FXR proteins. Overexpression of dfmr1 driven by the UAS-GAL4 system le ads to apoptotic cell loss in all adult Drosophila tissues examined. This p henotype is dependent on the activity of the KH domains. The ability to ind uce a dominant phenotype by overexpressing dfmr1 opens the possibility of u sing genetic approaches in Drosophila to identify the pathways in which the FMR1/FXR proteins function.