Vps54 regulates neuromuscular junction development and interacts genetically with Rab7 to control composition of the postsynaptic density.

Vps54 is a subunit of the Golgi-associated retrograde protein (GARP) complex, which is involved in tethering endosome-derived vesicles to the -Golgi network (TGN). In the wobbler mouse, a model for human motor neuron (MN) disease, reduction in the levels of Vps54 causes neurodegeneration. However, it is unclear how disruption of the GARP complex leads to MN dysfunction. To better understand the role of Vps54 in MNs, we have disrupted expression of the ortholog in and examined the impact on the larval neuromuscular junction (NMJ). Surprisingly, we show that both null mutants and MN-specific knockdown of leads to NMJ overgrowth. Reduction of partially disrupts localization of the t-SNARE, Syntaxin-16, to the TGN but has no visible impact on endosomal pools. MN-specific knockdown of in MNs combined with overexpression of the small GTPases Rab5, Rab7, or Rab11 suppresses the NMJ phenotype. Conversely, knockdown of combined with overexpression of dominant negative Rab7 causes NMJ and behavioral abnormalities including a decrease in postsynaptic Dlg and GluRIIB levels without any effect on GluRIIA. Taken together, these data suggest that controls larval MN axon development and postsynaptic density composition through a mechanism that requires Rab7.