Molecular and Genetic Analysis of the Drosophila Model of Fragile X Syndrome

Abstract

The Drosophila genome contains most genes known to be involved in heritable disease. The extraordinary genetic malleability of Drosophila, coupled to sophisticated imaging, electrophysiology and behavioral paradigms, has paved the way for insightful mechanistic studies on the causes of developmental and neurological disease as well as many possible interventions. Here, we focus on one of the most advanced examples of Drosophila genetic disease modeling, the Drosophila model of Fragile X Syndrome, which for the past decade has provided key advances into the molecular, cellular and behavioral defects underlying this devastating disorder. We discuss the multitude of RNAs and proteins that interact with the disease-causing FMR1 gene product, whose function is conserved from Drosophila to human. In turn, we consider FMR1 mechanistic relationships in non-neuronal tissues (germ cells and embryos), peripheral motor and sensory circuits, and central brain circuits involved in circadian clock activity and learning/memory.

Neuron class-specific requirements for Fragile X Mental Retardation Protein in critical period development of calcium signaling in learning and memory circuitry

“…1A; Tessier and Broadie, 2008; Tessier and Broadie, 2012). Following this window, FMRP levels rapidly fall to much lower steady-state expression in the mature brain (e.g.…”

“…As an essential component of neuronal excitability, calcium influx and subsequent regulation represents a prime target for FMRP function (Tessier and Broadie, 2012). We postulate that impaired critical period calcium regulation may underlie formation of the inappropriate neural architecture and synaptic connectivity characterizing the FXS disease state (Lohmann, 2009; Tessier and Broadie, 2008; Tessier and Broadie, 2011).…”

Two matrix metalloproteinase classes reciprocally regulate synaptogenesis

“…It is easy to envision how tissue-and development-stage-specific HS modifications could coordinate HSPG/Mmp-dependent functions, thereby differentially regulating diverse signaling events, which enable context-specific responses instructed by the extracellular environment. Future work will examine how dual inputs of the HSPG co-receptor function and how Mmp proteolytic cleavage coordinates Wnt trans-synaptic signaling during synaptogenesis, particularly in the context of our Fragile X syndrome (FXS) disease model (Coffee et al, 2010;Tessier and Broadie, 2012). Given that both loss or inhibition Mmp (Siller and Broadie, 2011) and correction of HSPG elevation (Friedman et al, 2013) independently alleviate synaptic defects in the FXS disease state, the overlapping mechanism provides an exciting avenue to therapeutic interventions for FXS and, potentially, related intellectual disability and autism spectrum disorders.…”

Transmission, Development, and Plasticity of Synapses

“…Dlg and Lgl are otherwise known to interact in epithelial cells where they cooperate to specify the basolateral membrane domain (Laprise and Tepass 2011). Lgl also interacts with FMRP (fragile X mental retardation protein), an RNA-binding protein that regulates translation of synaptic proteins (Tessier and Broadie 2012). In mutants of dfmr1, A-type receptors accumulate at the expense of B-type receptors, resulting in a shift of GluR composition (Pan and Broadie 2007).…”