Rescue of insulin signaling misregulation in a fly model of fragile x syndrome. Rachel E Monyak¹, Danielle Emerson¹, Yan Wang¹, Xiangzhong Zheng², Brian Schoenfeld³, Sean McBride¹, Amita Sehgal², Thomas Jongens¹. 1) Department of Genetics University of Pennsylvania Perelman School of Medicine Philadelphia, PA; 2) Howard Hughes Medical Institute and Department of Neuroscience University of Pennsylvania Perelman School of Medicine Philadelphia, PA; 3) Section of Molecular Cardiology Departments of Medicine and Molecular Pharmacology Albert Einstein College of Medicine Bronx, NY.

   Fragile x syndrome (FXS) is the most common inherited cause of intellectual disability. Patients with FXS exhibit cognitive defects, autism, sleep disorders, ADHD and epilepsy. These symptoms occur as the result of loss-of-function of a single gene, FMR1. To understand how FMR1 loss-of-function causes FXS, we study a Drosophila model of the disease in which the fly homolog of FMR1, dfmr1, does not function. The dfmr1 mutant fly displays phenotypes reminiscent of those seen in FXS patients including defects in memory, social behavior (seen by abnormal naïve courtship) and circadian rhythmicity. We found that expressing dfmr1 in the insulin-producing cells (IPCs) in the brain rescues the memory, naïve courtship and circadian defects of the dfmr1 mutant fly, indicating that dfmr1 expression in the IPCs is important for normal behavior. Since the IPCs regulate insulin signaling, we wondered whether this pathway could be misregulated in dfmr1 mutant flies. We found that dfmr1 mutant flies show increased levels of Drosophila insulin-like peptide 2 (dILP2) as well as increased PI3K and Akt activity, indicating that insulin signaling is increased in dfmr1 mutant flies. We further found that we could rescue the memory, naïve courtship and circadian rhythmicity defects by genetically reducing insulin signaling in the dfmr1 mutants. These results suggest that insulin signaling misregulation in dfmr1 mutant flies contributes to the behavioral abnormalities of this fragile x model and reveals another pathway involved in the pathogenesis of FXS.