Korkut Ceren, Ataman Bulent, Ramachandran Preethi, Ashley James, Barria Romina, Gherbesi Norberto, Budnik Vivian
Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Cell. 2009 Oct 16;139(2):393-404. doi: 10.1016/j.cell.2009.07.051.
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.
Wnt蛋白在发育过程以及成熟神经系统中发挥着关键作用。然而，Wnt蛋白在细胞间传递的机制一直尚不明确。在此，我们展示了一种通过释放含有Wnt结合蛋白Evenness Interrupted/Wntless/Sprinter（Evi/Wls/Srt）的类外泌体囊泡来进行Wnt传递的机制。我们发现，在果蝇幼虫神经肌肉接头（NMJ）处，Evi的突触前囊泡释放对于Wnt蛋白Wingless（Wg）的分泌是必需的。我们还表明，Evi在突触后Wnt接收细胞中自主发挥作用，将一种Wg受体相互作用蛋白dGRIP靶向至突触后位点。Evi功能丧失时，dGRIP无法正确靶向至突触位点，从而干扰突触后Wnt信号转导。这些发现揭示了一种此前未知的细胞机制，即分泌型Wnt蛋白通过含Evi的囊泡跨突触转运，并揭示了Evi在Wnt产生细胞和Wnt接收细胞中的转运功能。有关本文的视频摘要，请参阅在线提供的补充数据中的PaperFlick文件。
