A Localized Scaffold for cGMP Increase Is Required for Apical Dendrite Development.
A Localized Scaffold for cGMP Increase Is Required for Apical Dendrite Development.
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顶端树突发育需要用于增加 cGMP 的局部支架。
DOI：
10.1016/j.celrep.2020.03.083
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发表时间：
2020
期刊：
影响因子：
8.8
通讯作者：
Shelly,Maya
中科院分区：
文献类型：
--
作者：
Szczurkowska,Joanna;Lee,Seong-Il;Guo,Alan;Cwetsch,AndrzejW;Khan,Tanvir;Rao,Sneha;Walz,Gerd;Huber,TobiasB;Cancedda,Laura;Pautot,Sophie;Shelly,Maya
在培养的神经元中的研究已经确定，轴突特化指示神经元极化，并且是树突发育所必需的。然而，当轴突的形成被阻止时，体内树突的形成就会发生。促进树突发育的机制仍然是难以捉摸的。我们发现，顶端树突的发展是由本地化的环磷酸鸟苷（cGMP）合成复合物。我们发现，支架蛋白Scribble与cGMP合成酶可溶性鸟苷酸环化酶（sGC）和神经元型一氧化氮合酶（nNOS）。Scribble支架优先定位于树突并介导树突中的cGMP增加。这些事件由驱动蛋白KifC 2调节。Scribble、sGC-β1或KifC 2的敲除或破坏它们的结合可阻止树突中cGMP的增加，并导致顶端树突发育的严重缺陷。局部cGMP升高或sGC表达挽救了Scribble敲除对树突发育的影响，表明Scribble是cGMP的上游调节剂。在神经元极化过程中，树突发育由Scribble支架指导，该支架可能将细胞外信号与局部cGMP增加联系起来。
Studies in cultured neurons have established that axon specification instructs neuronal polarization and is necessary for dendrite development. However, dendrite formationin vivooccurs when axon formation is prevented. The mechanisms promoting dendrite development remain elusive. We find that apical dendrite development is directed by a localized cyclic guanosine monophosphate (cGMP)-synthesizing complex. We show that the scaffolding protein Scribble associates with cGMP-synthesizing enzymes soluble-guanylate-cyclase (sGC) and neuronal nitric oxide synthase (nNOS). The Scribble scaffold is preferentially localized to and mediates cGMP increase in dendrites. These events are regulated by kinesin KifC2. Knockdown of Scribble, sGC-β1, or KifC2 or disrupting their associations prevents cGMP increase in dendrites and causes severe defects in apical dendrite development. Local cGMP elevation or sGC expression rescues the effects of Scribble knockdown on dendrite development, indicating that Scribble is an upstream regulator of cGMP. During neuronal polarization, dendrite development is directed by the Scribble scaffold that might link extracellular cues to localized cGMP increase.