Fragile X syndrome (FXS) is caused solely by loss of fragile X mental retardation protein (FMRP), which binds mRNAs to mediate transcript stability and trafficking, and acts as a negative regulator

1400 INTRODUCTION Fragile X syndrome (FXS) is caused solely by loss of fragile X mental retardation protein (FMRP), which binds mRNAs to mediate transcript stability and trafficking, and acts as a negative regulator of translation (Laggerbauer et al., 2001; Li et al., 2001; Zhang et al., 2001; Lu et al., 2004; Muddashetty et al., 2007; Tessier and Broadie, 2008). Both humans with FXS and animal models of the disease (murine and Drosophila) exhibit synaptogenesis defects characterized by overgrowth and supernumerary synaptic contacts (Rudelli et al., 1985; Hinton et al., 1991; Gatto and Broadie, 2011; Tessier and Broadie, 2012). FXS disease models also exhibit defects in synaptic function, including elevated neurotransmission and altered activity-dependent plasticity (Zhang et al., 2001; Repicky and Broadie, 2009; Callan and Zarnescu, 2011; Gross et al., 2012). In the Drosophila FXS model, synaptic defects are rescued by introduction of human FMR1, but not the closely related FXR1 or FXR2 (Coffee et al., 2010; Tessier and Broadie, 2012), showing functional conservation of FMRP-dependent synaptogenic mechanisms. The numerous presynaptic and postsynaptic defects in the FXS disease state, which have often been first characterized in the Drosophila FXS model (Zhang et al., 2001; Pan et al., 2004; Pan and Broadie, 2007; Tessier and Broadie, 2012), have established clear roles for FMRP on both sides of the synaptic cleft. Conserved FMRP targets that have been functionally evaluated include presynaptic microtubule-associated protein 1B (MAP1B) (Zhang et al., 2001; Lu et al., 2004) and membrane-associated scaffold postsynaptic density protein of 95 kDa (PSD-95) (Zalfa et al., 2007; Muddashetty et al., 2011). Yet, the full spectrum of FMRP targets is unknown, and Drosophila remains an excellent model in which to study this complex regulation. Importantly, although some synaptogenic defects are rescued cell-autonomously, others require FMRP in the synaptic partner, demonstrating non-cell-autonomous requirements (Gatto and Broadie, 2008; Tessier and Broadie, 2012). Thus, FMRP might influence synaptogenesis via trans-synaptic signaling, regulating the cooperative differentiation of both sides of the synapse. Trans-synaptic signaling pathways have been particularly well characterized at the Drosophila neuromuscular junction (NMJ) model synapse (Bayat et al., 2011; Dani and Broadie, 2012; Koles and Budnik, 2012; Rohrbough et al., 2013). A classic WNT pathway involves presynaptic secretion of Wingless (Wg), anterograde activation of postsynaptic Frizzled-2 (Fz2) receptors, internalization and cleavage of the Fz2 C-terminus (Fz2-C), and finally Fz2-C nuclear import leading to modulation of synaptic structure and function (Packard et al., 2003; Salinas, 2003; Mathew et al., 2005; Koles and Budnik, 2012). Recent work has shown that Fz2-C localizes with translationally silenced ribonucleoprotein particles and aids in their trafficking outside the nucleus, facilitating local protein synthesis (Speese et al., 2012). A BMP pathway involves postsynaptic secretion of Glass bottom boat (Gbb), retrograde activation of presynaptic receptors containing Wishful thinking (Wit) and phosphorylation of the Mothers against decapentaplegic (MAD) transcription factor to similarly modulate synaptic structure Disease Models & Mechanisms 6, 1400-1413 (2013) doi:10.1242/dmm.012229