Modeling Fragile X Syndrome in Drosophila

Abstract

Intellectual disability (ID) and autism are hallmarks of Fragile X Syndrome (FXS), a hereditary neurodevelopmental disorder. The gene responsible for FXS is Fragile X Mental Retardation gene 1 (FMR1) encoding the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in RNA metabolism and modulating the expression level of many targets. Most cases of FXS are caused by silencing of FMR1 due to CGG expansions in the 5'-UTR of the gene. Humans also carry the FXR1 and FXR2 paralogs of FMR1 while flies have only one FMR1 gene, here called dFMR1, sharing the same level of sequence homology with all three human genes, but functionally most similar to FMR1. This enables a much easier approach for FMR1 genetic studies. Drosophila has been widely used to investigate FMR1 functions at genetic, cellular, and molecular levels since dFMR1 mutants have many phenotypes in common with the wide spectrum of FMR1 functions that underlay the disease. In this review, we present very recent Drosophila studies investigating FMRP functions at genetic, cellular, molecular, and electrophysiological levels in addition to research on pharmacological treatments in the fly model. These studies have the potential to aid the discovery of pharmacological therapies for FXS.

Keywords: Drosophila; FMR1; Fragile X Mental Retardation Protein; Fragile X Syndrome; behavior; dFRM1; mushroom bodies; neuromuscular junction.

Figure 1

dFMR1 expression in stage 14 Drosophila embryos. (A) Lateral view of a stage 14 embryo (middle focus) showing expression in the brain (arrowhead) and in the CNS (arrow). The salivary gland (asterisk) is non-specific background. (B) Lateral view of the same stage 14 embryo (surface focus) showing expression in several muscle precursors. The dFMR1 anti-sense probe was synthesized from the full length EST-clone LD09557 (Drosophila Genomics Resource Center, Bloomington, IN, USA) linearized with EcoRI and transcribed with the T7 RNA polymerase using the Riboprobe Combination System kit (Promega, Madison, WI) and the DIG RNA Labeling Mix (Roche, Indianapolis, IN). In situ hybridization was performed as in Tevy et al. (2014) except that SA-HRP and TSA were diluted at 1:250. Images were acquired at the SPIBOC imaging platform of the Institut Sophia Agrobiotech (Sophia Antipolis, France) on an Axioplan II microscope using the ZEN software (Carl Zeiss, Germany).