Based on these multiple lines of evidence, we hypothesized that the FMRP-MMP-HSPG intersection provides a coordinate mechanism for the pre- and postsynaptic defects characterizing the FXS disease state, with trans-synaptic signaling orchestrating synapse maturation across the synaptic cleft (McCabe et al., 2003; Korkut and Budnik, 2009; Ball et al., 2010; Budnik and Salinas, 2011; Rohrbough et al., 2013). Here, FMR1 is linked to fragile X syndrome.