RNA Polymerase 1-driven Transcription as a Mediator of BDNF-induced Neurite Outgrowth
RNA Polymerase 1-driven Transcription as a Mediator of BDNF-induced Neurite Outgrowth
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DOI：
10.1074/jbc.m110.170134
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发表时间：
2011-02-01
影响因子：
4.8
通讯作者：
Hetman, Michal
中科院分区：
文献类型：
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作者：
Gomes, Cynthia;Smith, Scott C.;Hetman, Michal
神经突起的生长对神经系统的发育至关重要。包括脑源性神经营养因子在内的神经营养因子是调节神经突起生长的细胞外信号。ERK1/2通路参与细胞内信号网络转导BDNF的前神经效应。在核仁中，RNA聚合酶-1(Pol1)介导的转录调控核糖体的生物发生，使细胞蛋白质合成和生长。因此，我们测试了Pol1是BDNF等神经前体信号的效应器的可能性。我们报道BDNF以ERK1/2依赖的方式促进大鼠前脑神经元Pol1介导的核仁转录。相反，在培养的海马神经元中，Pol1共激活因子转录起始因子1A(TIF1A)的敲除减弱了BDNF或ERK1/2诱导的突起生长。此外，在过表达的情况下，TIF1A的一个结构性活性突变体强烈促进了轴突的生长，包括增加了轴突的总长度和分支。最后，野生型TIF1A的过表达增强了ERK1/2激活的前神经元效应。这些观察表明，Pol1介导的核仁转录调控轴突生长，并在BDNF激活的ERK1/2途径中发挥主要的神经突起效应。因此，神经系统的发育似乎严重依赖于核仁。
Neurite outgrowth is essential for development of the nervous system. Neurotrophins including BDNF are among extracellular signals that regulate neurite outgrowth. The ERK1/2 pathway contributes to intracellular signaling networks transducing the pro-neuritic effects of BDNF. In the nucleolus, RNA polymerase-1 (Pol1)-mediated transcription regulates ribosomal biogenesis, enabling cellular protein synthesis and growth. Hence, we tested the possibility that Pol1 is an effector for pro-neuritic signals such as BDNF. We report that Pol1-mediated nucleolar transcription was increased by BDNF in an ERK1/2-dependent manner in rat forebrain neurons. Conversely, in cultured hippocampal neurons, knockdown of a Pol1 coactivator, transcription initiation factor 1A (TIF1A), attenuated BDNF- or ERK1/2-induced neurite outgrowth. Also, upon overexpression, a constitutively active mutant of TIF1A strongly promoted neurite outgrowth, including increases in total neurite length and branching. Finally, overexpression of wild-type TIF1A enhanced the pro-neuritic effects of ERK1/2 activation. These observations indicate that the Pol1-mediated nucleolar transcription regulates neurite outgrowth and serves as a major pro-neuritic effector of the BDNF-activated ERK1/2 pathway. Thus, development of the nervous system appears critically dependent on the nucleolus.