High content screening of cortical neurons identifies novel regulators of axon growth.
High content screening of cortical neurons identifies novel regulators of axon growth.
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DOI：
10.1016/j.mcn.2010.02.002
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发表时间：
2010-05
影响因子：
3.5
通讯作者：
Lemmon, Vance P.
中科院分区：
文献类型：
--
作者：
Blackmore, Murray G.;Moore, Darcie L.;Smith, Robin P.;Goldberg, Jeffrey L.;Bixby, John L.;Lemmon, Vance P.
关键词：
中枢神经系统中的神经元在成熟时失去了轴突再生的内在能力，并且广泛假设基因表达的变化是负责的。测试这一假设并识别相关基因一直具有挑战性，因为在CNS神经元中有数百至数千个基因受到发育调控，但只有一小部分可能与轴突生长相关。在这里，我们使用自动化高含量分析（HCA）的方法，功能测试743质粒编码发育调控基因的神经突生长测定使用出生后的皮层神经元。我们鉴定了生长抑制剂（Ephexin、醛缩酶A、溶质载体2A3和嵌合蛋白）和生长增强剂（Doublecortin、Doublecortin样、Kruppel样因子6和CaM激酶II γ），其中一些调节已建立的生长机制，如微管动力学和小GT3信号传导。有趣的是，只有一个例外，生长抑制基因在发育过程中上调，而生长促进基因下调。这些数据为基因表达的发育变化控制神经突生长的假说提供了重要的支持，并确定了促进神经突生长的潜在新基因靶点。
Neurons in the central nervous system lose their intrinsic capacity for axon regeneration as they mature, and it is widely hypothesized that changes in gene expression are responsible. Testing this hypothesis and identifying the relevant genes has been challenging because hundreds to thousands of genes are developmentally regulated in CNS neurons, but only a small subset are likely relevant to axon growth. Here we used automated high content analysis (HCA) methods to functionally test 743 plasmids encoding developmentally regulated genes in neurite outgrowth assays using postnatal cortical neurons. We identified both growth inhibitors (Ephexin, Aldolase A, Solute Carrier 2A3, and Chimerin), and growth enhancers (Doublecortin, Doublecortin-like, Kruppel-like Factor 6, and CaM-Kinase II gamma), some of which regulate established growth mechanisms like microtubule dynamics and small GTPase signaling. Interestingly, with only one exception the growth-suppressing genes were developmentally upregulated, and the growth-enhancing genes downregulated. These data provide important support for the hypothesis that developmental changes in gene expression control neurite outgrowth, and identify potential new gene targets to promote neurite outgrowth.
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