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首页> 外文学位 >Bidirectional control of dendritic mRNA translation, glutamate receptor expression, and synapse structure by the CPEB-associated polyadenylation machinery.
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Bidirectional control of dendritic mRNA translation, glutamate receptor expression, and synapse structure by the CPEB-associated polyadenylation machinery.

机译：通过CPEB相关的聚腺苷酸化机制双向控制树突状mRNA的翻译，谷氨酸受体的表达和突触结构。

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摘要

Neurons are highly polarized cells that extend elaborate dendritic arbors and have thousands of synaptic inputs. The post-transcriptional control of gene expression through dendritic mRNA localization and local protein synthesis is an important means for regulating postsynaptic protein expression. Moreover, translational control of dendritic mRNAs is essential for certain forms of synaptic plasticity, learning, and memory. CPEB (cytoplasmic polyadenylation element binding protein) is one RNA binding protein that regulates local translation in dendrites as well as synaptic structure and function. However, the mechanism by which it regulates these processes is unknown. Herein, we identify a poly(A) polymerase, a deadenylase, and the translation inhibitory factor neuroguidin as components of a dendritic CPEB-associated polyadenylation complex. Synaptic stimulation induces phosphorylation of CPEB, expulsion of the deadenylase from the ribonucleoprotein complex, and mRNA polyadenylation in dendrites. Furthermore, these CPEB-associated translation factors bidirectionally regulate dendritic spine morphology as well as AMPA receptor surface expression in cultured hippocampal neurons. One CPEB target mRNA is that encoding GluN2A, which is an NMDA receptor subunit and a critical regulator of synapse function and plasticity. We found that GluN2A mRNA is localized to dendrites and associates with CPEB. The dendritic transport and local translation of GluN2A mRNA is regulated target sequence within GluN2A mRNA. The CPEB-associated poly(A) polymerase promotes dendritic GluN2A protein expression and surface expression of GluN2A-containing NMDA receptors; whereas, the negative translation factor neuroguidin inhibits GluN2A expression in dendrites and at the cell surface. Moreover, protein synthesis and this poly(A) polymerase are required for activity-induced translation of GluN2A and membrane insertion of GluN2A-containing NMDA receptors. These results identify a pivotal role for dendritic mRNA polyadenylation and the opposing effects of CPEB-associated translation factors in regulating receptor expression and synapse structure at glutamatergic synapses as well as activity-induced membrane insertion of NMDA receptors during synaptic plasticity.
机译：神经元是高度极化的细胞，可延伸复杂的树突状树突并具有数千个突触输入。通过树突状mRNA定位和局部蛋白质合成的基因表达的转录后控制是调节突触后蛋白质表达的重要手段。此外，树突状mRNA的翻译控制对于某些形式的突触可塑性，学习和记忆至关重要。 CPEB（胞质聚腺苷酸化元素结合蛋白）是一种RNA结合蛋白，可调节树突中的局部翻译以及突触结构和功能。但是，调节这些过程的机制尚不清楚。在这里，我们确定了poly（A）聚合酶，腺苷酸酶和翻译抑制因子neuroguidin作为树突状CPEB相关的聚腺苷酸化复合物的组成部分。突触刺激诱导CPEB磷酸化，从核糖核蛋白复合物中排出死烯基化酶，并在树突中诱导mRNA多聚腺苷酸化。此外，这些CPEB相关的翻译因子双向调节培养的海马神经元中的树突棘形态以及AMPA受体表面表达。一种CPEB靶mRNA是编码GluN2A的mRNA，GluN2A是NMDA受体亚基，是突触功能和可塑性的关键调节因子。我们发现，GluN2A mRNA定位于树突并与CPEB缔合。 GluN2A mRNA的树突状转运和局部翻译是GluN2A mRNA中受调控的靶序列。 CPEB相关的聚（A）聚合酶促进树突状GluN2A蛋白表达和含GluN2A的NMDA受体的表面表达。负翻译因子Neuroguidin抑制树突状细胞和细胞表面GluN2A的表达。此外，蛋白质合成和这种聚（A）聚合酶是活性诱导的GluN2A的翻译和含GluN2A的NMDA受体的膜插入所必需的。这些结果确定了树突状mRNA聚腺苷酸的关键作用和CPEB相关翻译因子在调节谷氨酸能突触的受体表达和突触结构以及在突触可塑性期间活性诱导的NMDA受体膜插入方面的相反作用。

著录项

  • 作者

    Swanger, Sharon A.;

  • 作者单位

    Emory University.;

  • 授予单位 Emory University.;
  • 学科 Biology Neuroscience.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 281 p.
  • 总页数 281
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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