N-docosahexaenoylethanolamine regulates Hedgehog signaling and promotes growth of cortical axons
N-docosahexaenoylethanolamine regulates Hedgehog signaling and promotes growth of cortical axons
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DOI：
10.1242/bio.013425
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发表时间：
2015-12-15
期刊：
影响因子：
2.4
通讯作者：
Kim, Hee-Yong
中科院分区：
文献类型：
--
作者：
Kharebava, Giorgi;Rashid, Mohammad A.;Kim, Hee-Yong
轴突发生是建立神经元连接的过程，是大脑功能的核心。大脑中特别富集的二十二碳六烯酸 (DHA, 22:6n-3) 衍生的代谢物在轴突发育中的作用尚未得到解决。在这项研究中，我们测试了突触酰胺（N-二十二碳六烯酰乙醇胺）（DHA 的内源性代谢产物）是否影响培养的皮质神经元的轴突生长。我们发现突触酰胺增加了平均轴突长度，抑制 GLI 家族锌指 1 (GLI1) 转录和声波刺猬 (Shh) 靶基因表达，同时诱导 cAMP 升高。 Shh 通路的调节剂环杷明也产生了类似的效果。相反，Shh 拮抗 cAMP 的升高并阻止突触酰胺介导的轴突长度增加。由平滑化 (SMO) 激动剂 (SAG) 激活的 Shh 通路或 SMO 的过表达不会抑制突触酰胺或环巴明介导的轴突生长。相反，腺苷酸环化酶抑制剂 SQ22536 消除了突触酰胺介导的轴突生长，表明该过程需要 cAMP 升高。我们的研究结果表明，突触酰胺促进轴突生长，而 Shh 通过不依赖于 SMO 的非典型途径拮抗突触酰胺介导的 cAMP 升高和轴突生长。
Axonogenesis, a process for the establishment of neuron connectivity, is central to brain function. The role of metabolites derived from docosahexaenoic acid (DHA, 22:6n-3) that is specifically enriched in the brain, has not been addressed in axon development. In this study, we tested if synaptamide (N-docosahexaenoylethanolamine), an endogenous metabolite of DHA, affects axon growth in cultured cortical neurons. We found that synaptamide increased the average axon length, inhibited GLI family zinc finger 1 (GLI1) transcription and sonic hedgehog (Shh) target gene expression while inducing cAMP elevation. Similar effects were produced by cyclopamine, a regulator of the Shh pathway. Conversely, Shh antagonized elevation of cAMP and blocked synaptamide-mediated increase in axon length. Activation of Shh pathway by a smoothened (SMO) agonist (SAG) or overexpression of SMO did not inhibit axon growth mediated by synaptamide or cyclopamine. Instead, adenylate cyclase inhibitor SQ22536 abolished synaptamide-mediated axon growth indicating requirement of cAMP elevation for this process. Our findings establish that synaptamide promotes axon growth while Shh antagonizes synaptamide-mediated cAMP elevation and axon growth by a SMO-independent, non-canonical pathway.