Neuropilin1 is a direct downstream target of Nurr1 in the developing brain stem
Neuropilin1 is a direct downstream target of Nurr1 in the developing brain stem
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DOI：
10.1111/j.1471-4159.2006.03829.x
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发表时间：
2006-06-01
影响因子：
4.7
通讯作者：
Perlmann, Thomas
中科院分区：
文献类型：
--
作者：
Hermanson, Elisabet;Borgius, Lotta;Perlmann, Thomas
孤儿核受体Nurr 1在发育和成人中枢神经系统中表达。先前的研究表明，Nurr 1对中脑多巴胺神经元的产生至关重要。此外，Nurr 1对与脑干相关的呼吸功能至关重要。Nurr 1调控的基因很少被发现，目前还不清楚Nurr 1如何影响神经元的功能和发育。为了鉴定新的Nurr 1靶基因，我们在多巴胺能MN 9D细胞系中寻找调节基因。这些实验确定了神经纤毛蛋白-1（Nrp 1），一种参与轴突导向和血管生成的受体蛋白，作为一种新的Nurr 1靶基因。Nurr 1在MN 9D细胞中迅速上调Nrp 1的表达，原位杂交分析显示Nrp 1与Nurr 1在脑干运动背核中共表达。重要的是，在Nurr 1基因敲除小鼠中，Nrp 1表达在该区域下调。此外，在Nrp 1启动子中鉴定了两个功能性Nurr 1结合位点，并且发现Nurr 1在MN 9D细胞中被募集到这些位点，进一步支持Nrp 1是Nurr 1的直接下游靶标。总之，我们的研究结果表明，Nurr 1可能会影响轴突导向和/或血管生成的过程中，通过调节Nrp 1的表达。
The orphan nuclear receptor Nurr1 is expressed in the developing and adult central nervous system. Previous studies have shown that Nurr1 is essential for the generation of midbrain dopamine neurons. Furthermore, Nurr1 is critical for respiratory functions associated with the brain stem. Very few Nurr1 regulated genes have been identified and it remains unclear how Nurr1 influences the function and development of neurons. To identify novel Nurr1 target genes we have searched for regulated genes in the dopaminergic MN9D cell line. These experiments identified Neuropilin-1 (Nrp1), a receptor protein involved in axon guidance and angiogenesis, as a novel Nurr1 target gene. Nrp1 expression was rapidly up-regulated by Nurr1 in MN9D cells and in situ hybridization analysis showed that Nrp1 was coexpressed with Nurr1 in the brain stem dorsal motor nucleus. Importantly, Nrp1 expression was down-regulated in this area in Nurr1 null mice. Moreover, two functional Nurr1 binding sites were identified in the Nrp1 promoter and Nurr1 was found to be recruited to these sites in MN9D cells, further supporting that Nrp1 is a direct downstream target of Nurr1. Taken together, our findings suggest that Nurr1 might influence the processes of axon guidance and/or angiogenesis via the regulation of Nrp1 expression.