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首页> 外文学位 >Overexpression of the RNA-binding protein HuD increases the stability of GAP-43mRNA in dentate granule cells of adult mice leading to aberrant synapse formation.
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Overexpression of the RNA-binding protein HuD increases the stability of GAP-43mRNA in dentate granule cells of adult mice leading to aberrant synapse formation.

机译：RNA结合蛋白HuD的过表达增加了成年小鼠齿状颗粒细胞中GAP-43mRNA的稳定性，导致异常突触形成。

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摘要

With the sequencing of the human genome and the advent of proteomics a significant discrepancy has been brought to the attention of many scientists: there is a great disparity in the number of genes compared to the number of proteins we make. The difference is accounted for by post-transcriptional regulation, which is being recognized as an important mechanism for altering gene expression. Using GAP-43 as a model post-transcriptionally regulated mRNA, I examined the role of HuD-mediated stability of GAP-43 mRNA in the adult murine brain and a number of the downstream physiological consequences. Dentate granule cells (DGCs) of the adult mouse hippocampus transcribe the GAP-43 gene, yet do not express mRNA or protein. Interestingly, these cells also do not express the RNA-binding protein HuD. DGCs provide the perfect model system to test the function of HuD in post-transcriptional regulation of GAP-43. I found that HuD overexpressing (HUD-Tg) mice express HuD in DGCs and have high levels of GAP-43 mRNA, while levels of transcription were not changed. This suggests that the mRNA is more stable. Confirming this idea, in vitro transcribed GAP-43 mRNA was more stable in extracts from HuD-Tg mice. In addition, I found that GAP-43 is translated in these cells and the protein is targeted to their axons, the mossy fibers. There was also an increase in GAP-43 protein levels in the projections from the other brain areas to the hippocampus. While gross brain morphology was similar to that of wildtype mice, HuD-Tg mice exhibit an increase in mossy fibers of the infrapyramidal bundle that are Timm's stain positive, indicating that they make functional contact with nearby dendrites. The HuD-induced upregulation of GAP-43 and the structural changes highlight the importance of regulating mRNA turnover and stability.
机译：随着人类基因组测序的发展和蛋白质组学的出现，许多科学家引起了巨大的差异：与我们制造的蛋白质数量相比，基因数量存在巨大差异。差异是由转录后调控引起的，转录后调控被认为是改变基因表达的重要机制。使用GAP-43作为转录后调控mRNA的模型，我研究了HuD介导的GAP-43 mRNA在成年鼠脑中的稳定性以及许多下游生理后果。成年小鼠海马的齿状颗粒细胞（DGC）转录GAP-43基因，但不表达mRNA或蛋白质。有趣的是，这些细胞也不表达RNA结合蛋白HuD。 DGC提供了完善的模型系统来测试HuD在GAP-43转录后调控中的功能。我发现HuD过表达（HUD-Tg）小鼠在DGC中表达HuD，并具有高水平的GAP-43 mRNA，而转录水平没有变化。这表明mRNA更稳定。证实了这一想法，体外转录的GAP-43 mRNA在来自HuD-Tg小鼠的提取物中更稳定。此外，我发现GAP-43在这些细胞中被翻译，并且该蛋白质靶向它们的轴突，即苔藓纤维。从其他大脑区域到海马的投射中，GAP-43蛋白水平也有所增加。尽管总体脑部形态与野生型小鼠相似，但HuD-Tg小鼠的锥体束丛生苔纤维增加，而Timm染色呈阳性，表明它们与附近的树突进行功能性接触。 HuD诱导的GAP-43上调和结构变化突出了调节mRNA转换和稳定性的重要性。

著录项

  • 作者

    Tanner, Daniel C.;

  • 作者单位

    The University of New Mexico.;

  • 授予单位 The University of New Mexico.;
  • 学科 Biology Neuroscience.; Biology Molecular.; Biology Cell.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 107 p.
  • 总页数 107
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;分子遗传学;细胞生物学;
  • 关键词

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