Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless.

Wnts play pivotal roles during development and in the mature nervous system. However, the mechanism by which Wnts traffic between cells has remained elusive. Here we demonstrate a mechanism of Wnt transmission through release of exosome-like vesicles containing the Wnt-binding protein Evenness Interrupted/Wntless/Sprinter (Evi/Wls/Srt). We show that at the Drosophila larval neuromuscular junction (NMJ), presynaptic vesicular release of Evi is required for the secretion of the Wnt, Wingless (Wg). We also show that Evi acts cell-autonomously in the postsynaptic Wnt-receiving cell to target dGRIP, a Wg-receptor-interacting protein, to postsynaptic sites. Upon Evi loss of function, dGRIP is not properly targeted to synaptic sites, interfering with postsynaptic Wnt signal transduction. These findings uncover a previously unknown cellular mechanism by which a secreted Wnt is transported across synapses by Evi-containing vesicles and reveal trafficking functions of Evi in both the Wnt-producing and the Wnt-receiving cells. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.

Postsynaptic membrane addition depends on the Discs-Large-interacting t-SNARE Gtaxin.

Targeted membrane addition is a hallmark of many cellular functions. In the nervous system, modification of synaptic membrane size has a major impact on synaptic function. However, because of the complex shape of neurons and the need to target membrane addition to very small and polarized synaptic compartments, this process is poorly understood. Here, we show that Gtaxin (GTX), a Drosophila t-SNARE (target-soluble N-ethylmaleimide-sensitive factor attachment protein receptor), is required for expansion of postsynaptic membranes during new synapse formation. Mutations in gtx lead to drastic reductions in postsynaptic membrane surface, whereas gtx upregulation results in the formation of complex membrane structures at ectopic sites. Postsynaptic GTX activity depends on its direct interaction with Discs-Large (DLG), a multidomain scaffolding protein of the PSD-95 (postsynaptic density protein-95) family with key roles in cell polarity and formation of cellular junctions as well as synaptic protein anchoring and trafficking. We show that DLG selectively determines the postsynaptic distribution of GTX to type I, but not to type II or type III boutons on the same cell, thereby defining sites of membrane addition to this unique set of glutamatergic synapses. We provide a mechanistic explanation for selective targeted membrane expansion at specific synaptic junctions.

Deficiency of the zinc finger protein ZPR1 causes neurodegeneration.

Mutations that cause reduced expression of the full-length Survival Motor Neurons (SMN) protein are a major cause of spinal muscular atrophy (SMA), a disease characterized by degeneration of the alpha-motor neurons in the anterior horn of the spinal cord. The severity of SMA may be influenced by the actions of modifier genes. One potential modifier gene is represented by ZPR1, which is down-regulated in patients with SMA and encodes a zinc finger protein that interacts with complexes formed by SMN. To test the functional significance of ZPR1 gene down-regulation, we examined a mouse model with targeted ablation of the Zpr1 gene. We report that ZPR1-deficient mice exhibit axonal pathology and neurodegeneration. These data identify ZPR1 deficiency as a contributing factor in neurodegenerative disorders.