A sympathetic neuron autonomous role for Egr3-mediated gene regulation in dendrite morphogenesis and target tissue innervation.
A sympathetic neuron autonomous role for Egr3-mediated gene regulation in dendrite morphogenesis and target tissue innervation.
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DOI：
10.1523/jneurosci.5481-12.2013
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发表时间：
2013-03-06
期刊：
影响因子：
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通讯作者：
Tourtellotte WG
中科院分区：
文献类型：
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作者：
Quach DH;Oliveira-Fernandes M;Gruner KA;Tourtellotte WG
Egr3是一种神经生长因子(NGF)诱导的转录调节因子，对交感神经系统的正常发育至关重要。在胚系中缺乏Egr3的小鼠有交感目标组织神经支配异常和生理性交感神经功能障碍，类似于患有自主神经障碍的人类。然而，由于Egr3被广泛表达并具有多效性，目前还不清楚它是否在交感神经元中发挥作用，如果是的话，它调节哪些靶基因来促进靶组织的神经支配。在这里，我们证明了交感神经元中Egr3的表达是其正常神经支配所必需的，因为在NGF处理时，缺乏Egr3的交感神经元会出现轴突生长异常，而交感神经元限制性Egr3消融的小鼠在所有组织中都有类似于缺乏Egr3的小鼠的靶组织神经支配异常。对交感神经元进行的微阵列分析发现，在缺少Egr3的情况下，许多靶基因被解除了调控，其中一些最显著的被解除调控的基因在轴突发生、树突形成和轴突引导中发挥了作用。使用一种新的遗传技术对随机标记的交感神经元亚群中的轴突和树突进行可视化，我们发现Egr3在调节交感神经元树突形态和终末轴突分支方面具有重要作用，但在调节交感神经对其靶点的引导方面没有重要作用。综上所述，这些结果表明，Egr3在交感神经系统发育中具有交感神经元自主作用，涉及调节下游靶基因，影响交感神经元树突和轴突的生长和分支。
Egr3 is a nerve growth factor (NGF)-induced transcriptional regulator that is essential for normal sympathetic nervous system development. Mice lacking Egr3 in the germline have sympathetic target tissue innervation abnormalities and physiologic sympathetic dysfunction similar to humans with dysautonomia. However, since Egr3 is widely expressed and has pleiotropic function, it has not been clear whether it has a role within sympathetic neurons and if so, what target genes it regulates to facilitate target tissue innervation. Here, we show that Egr3 expression within sympathetic neurons is required for their normal innervation since isolated sympathetic neurons lacking Egr3 have neurite outgrowth abnormalities when treated with NGF and mice with sympathetic neuron-restricted Egr3 ablation have target tissue innervation abnormalities similar to mice lacking Egr3 in all tissues. Microarray analysis performed on sympathetic neurons identified many target genes deregulated in the absence of Egr3, with some of the most significantly deregulated genes having roles in axonogenesis, dendritogenesis, and axon guidance. Using a novel genetic technique to visualize axons and dendrites in a subpopulation of randomly labeled sympathetic neurons, we found that Egr3 has an essential role in regulating sympathetic neuron dendrite morphology and terminal axon branching, but not in regulating sympathetic axon guidance to their targets. Together, these results indicate that Egr3 has a sympathetic neuron autonomous role in sympathetic nervous system development that involves modulating downstream target genes affecting the outgrowth and branching of sympathetic neuron dendrites and axons.