| dc.description.abstract | Fragile X syndrome (FXS) is an inherited intellectual disability and autism spectrum disorders. Most FXS patients have a total loss of Fragile X Mental Retardation Protein (FMRP) resulting from the epigenetic silence of Fragile X Mental Retardation 1 (FMR1). Loss of FMRP leads to impaired intercellular communication in the nervous system. To explore genetic and molecular mechanisms in this neurodevelopmental disorder, I studied the Drosophila FXS disease model, including muscle-to-neuron signaling at the neuromuscular junction (NMJ) as well as neuron-to-glia intercellular signaling in the central nervous system (CNS). At the NMJ, I found that postsynaptic muscle FMRP interacts with Staufen-Coracle signaling to restrict glutamate receptor A (GluRIIA) levels on muscle, which, in turn, acts to transcellularly limit phosphorylated Mother against Decapentaplegic (pMad) in presynaptic boutons to inhibit synaptic terminal formation. In the CNS, I found neuronal FMRP works through pMad, insulin receptor (InR), and phosphorylated protein kinase B (pAkt) signaling, in a network regulating Pretaporter and Amyloid Precursor Protein-like (APPL) communication directing glial phagocytosis for neuron pruning. These discoveries reveal principles of FMRP-dependent intercellular signaling pathways for neurodevelopment, identifying potential avenues for Fragile X syndrome treatments. | |
