Fragile X Mental Retardation Protein Regulates Trans-Synaptic Signaling. Samuel H. Friedman, Neil Dani, Kendal Broadie. Department of Biological Sciences, Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37212 USA.

   Fragile X Syndrome (FXS), the most common inherited determinant of intellectual disability and autism spectrum disorders, is caused by the loss of the fragile x mental retardation 1 (fmr1) gene product (FMRP), an RNA-binding translational repressor. Screens for upregulated neuronal proteins in Drosophila fmr1 (dfmr1) null mutants reveal strong elevation of two synaptic heparan sulfate proteoglycans (HSPG); GPI-anchored glypican Dally-like (Dlp) and transmembrane Syndecan (Sdc). Our recent work has shown that Dlp and Sdc act as co-receptors that regulate both extracellular ligand abundance and intracellular signal transduction in trans-synaptic pathways driving synaptogenesis. Consistently, dfmr1 null synapses exhibit altered WNT signaling, with changes in both Wingless (Wg) ligand abundance and downstream Frizzled-2 (Fz2) receptor C-terminal nuclear import. Similarly, a parallel anterograde signaling ligand, Jelly Belly (Jeb), together with downstream ERK phosphorylation (dpERK), is altered at dfmr1 null synapses. In contrast, the retrograde BMP ligand Glass Bottom Boat (Gbb) and downstream signaling via transcription factor MAD phosphorylation (pMAD) is not affected, revealing the mechanism to be selective for anterograde pathways. These dysregulations in trans-synaptic signaling pose exciting new insights into the synaptogenesis and functional phenotypes correlated with the loss of FMRP in FXS.