Wnt signalling tunes neurotransmitter release by directly targeting Synaptotagmin-1.
Wnt signalling tunes neurotransmitter release by directly targeting Synaptotagmin-1.
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DOI：
10.1038/ncomms9302
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发表时间：
2015-09-24
影响因子：
16.6
通讯作者：
Salinas PC
中科院分区：
文献类型：
--
作者：
Ciani L;Marzo A;Boyle K;Stamatakou E;Lopes DM;Anane D;McLeod F;Rosso SB;Gibb A;Salinas PC
突触释放机制的功能组装是众所周知的；然而，信号因子如何调节这一过程仍然未知。最近的研究表明 Wnts 在突触前功能中发挥作用。为了研究所涉及的机制，我们研究了释放机制蛋白与 Dishevelled-1 (Dvl1) 的相互作用，Dishevelled-1 (Dvl1) 是一种决定 Wnt 作用的细胞部位的支架蛋白。在这里，我们表明 Dvl1 直接与 Synaptotagmin-1 (Syt-1) 相互作用，并间接与 SNARE 蛋白 SNAP25 和 Syntaxin (Stx-1) 相互作用。重要的是，Dvl1 与 Syt-1 的相互作用（受 Wnts 调节）可调节神经递质的释放。此外，Wnt 信号传导缺陷小鼠的突触前末梢表现出释放概率降低，并且无法维持高频释放。一致地，易于释放的池大小和 SNARE 复合体的形成都会减少。我们的研究表明 Wnt 信号传导调节神经递质释放，并将 Syt-1 确定为分泌信号蛋白调节的靶标。信号蛋白动态调节神经递质释放的机制仍知之甚少。在这里，Ciani 等人。显示 Wnt 信号传导通过与 Dishevelled-1 和突触囊泡钙传感器 Synaptotagmin-1 的直接相互作用，以活性依赖的方式影响囊泡池的可用性。
The functional assembly of the synaptic release machinery is well understood; however, how signalling factors modulate this process remains unknown. Recent studies suggest that Wnts play a role in presynaptic function. To examine the mechanisms involved, we investigated the interaction of release machinery proteins with Dishevelled-1 (Dvl1), a scaffold protein that determines the cellular locale of Wnt action. Here we show that Dvl1 directly interacts with Synaptotagmin-1 (Syt-1) and indirectly with the SNARE proteins SNAP25 and Syntaxin (Stx-1). Importantly, the interaction of Dvl1 with Syt-1, which is regulated by Wnts, modulates neurotransmitter release. Moreover, presynaptic terminals from Wnt signalling-deficient mice exhibit reduced release probability and are unable to sustain high-frequency release. Consistently, the readily releasable pool size and formation of SNARE complexes are reduced. Our studies demonstrate that Wnt signalling tunes neurotransmitter release and identify Syt-1 as a target for modulation by secreted signalling proteins. The mechanisms by which signalling proteins dynamically modulate neurotransmitter release remain poorly understood. Here, Ciani et al. show Wnt signalling influences vesicle pool availability in an activity-dependent manner via direct interactions with Dishevelled-1 and the synaptic vesicle calcium sensor Synaptotagmin-1.