Destabilization of axonal mRNAs by KHSRP complexes during axon regeneration

轴突再生过程中 KHSRP 复合物导致轴突 mRNA 不稳定

基本信息

项目摘要

SUMMARY This application asks how localized mRNA stability modifies axonal regeneration capacity, focusing on contributions of the RNA binding protein [RBP] KHSRP. The nervous system makes extensive use of post- transcriptional mechanisms to regulate cellular proteomes in response to extracellular stimuli and physiologic environments during development, function, & in response to axonal injury. Since one mRNA can be translated into protein many times over, how long a given mRNA is available for translation impacts the amount of protein generated from that mRNA. Stability of mRNAs is indeed regulated, with interactions with RBPs stabilizing & destabilizing different mRNAs, as well as interactions with microRNAs targeting some targets for degradation. Translation of mRNAs clearly supports axon regeneration, but we have little knowledge for how stability of axonal mRNAs is locally regulated. We have shown that the RBPs HuD (also called ELAVL4) and KHSRP (also called FUBP2, MARTA1, & ZBP2) compete for binding to neuronal mRNAs with AU-rich elements, where HuD interaction stabilizes and KHSRP interaction destabilizes target mRNAs. At the molecular level, this interaction is impacted by an mRNA’s affinity for binding to HuD or KHSRP. Our work over years 01-05 show that loss of KHSRP increases KHSRP target mRNA levels, causes excessive axonal and dendritic growth, impairs memory consolidation in hippocampus & prefrontal cortex, and increases presynaptic activity in prefrontal cortex and hippocampus. KHSRP is expressed into adulthood, and we surprisingly find that axonal KHSRP levels rapidly increase in peripheral nerves after injury. This increase in axonal KHSRP occurs through intra-axonal translation of its encoding mRNA. Our preliminary data indicate that KHSRP knockout mice show accelerated nerve regeneration pointing to axon-intrinsic functions for KHSRP in regeneration. Based on these observations, we hypothesize that axonal KHSRP controls the rates of axon regeneration through regulation of localized mRNA stability. We will test this hypothesis with the following specific aims: 1) Does KHSRP regulate PNS axon regeneration through a neuron intrinsic mechanism? 2) Does increased axonal KHSRP limit axon regeneration by destabilizing axonal mRNAs encoding regeneration-associated proteins? and 3) Does KHSRP’s protein interactome influence its intra-axonal functions? Completion of the studies here will begin to fill this knowledge gap by focusing on RNA-protein interactions initiated in axons that can affect mRNA survival. This will provide the first subcellular analyses of RBP domain-specific RNA regulons and will bring the first systematic assessment for contributions of RNA survival to peripheral nerve regeneration.
总结

项目成果

期刊论文数量(0)
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JEFFERY L TWISS其他文献

JEFFERY L TWISS的其他文献

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{{ truncateString('JEFFERY L TWISS', 18)}}的其他基金

Role of Stress Granule Protein Aggregation in Axon Regeneration
应激颗粒蛋白聚集在轴突再生中的作用
  • 批准号:
    10265401
  • 财政年份:
    2020
  • 资助金额:
    $ 40.74万
  • 项目类别:
Role of Stress Granule Protein Aggregation in Axon Regeneration
应激颗粒蛋白聚集在轴突再生中的作用
  • 批准号:
    10406395
  • 财政年份:
    2020
  • 资助金额:
    $ 40.74万
  • 项目类别:
Role of Stress Granule Protein Aggregation in Axon Regeneration
应激颗粒蛋白聚集在轴突再生中的作用
  • 批准号:
    10447127
  • 财政年份:
    2020
  • 资助金额:
    $ 40.74万
  • 项目类别:
Role of Stress Granule Protein Aggregation in Axon Regeneration
应激颗粒蛋白聚集在轴突再生中的作用
  • 批准号:
    10647839
  • 财政年份:
    2020
  • 资助金额:
    $ 40.74万
  • 项目类别:
Role of Stress Granule Protein Aggregation in Axon Regeneration
应激颗粒蛋白聚集在轴突再生中的作用
  • 批准号:
    10030563
  • 财政年份:
    2020
  • 资助金额:
    $ 40.74万
  • 项目类别:
Destabilization of axonal mRNAs by KHSRP complexes during axon regeneration
轴突再生过程中 KHSRP 复合物导致轴突 mRNA 不稳定
  • 批准号:
    10666545
  • 财政年份:
    2015
  • 资助金额:
    $ 40.74万
  • 项目类别:
Destabilization of axonal mRNAs by KHSRP complexes during axon regeneration
轴突再生过程中 KHSRP 复合物导致轴突 mRNA 不稳定
  • 批准号:
    10430242
  • 财政年份:
    2015
  • 资助金额:
    $ 40.74万
  • 项目类别:
Systems dynamics of intracellular communication (Spatial 2011)
细胞内通讯的系统动力学(Spatial 2011)
  • 批准号:
    8129400
  • 财政年份:
    2011
  • 资助金额:
    $ 40.74万
  • 项目类别:
REGULATION OF AXONAL PROTEIN SYNTHESIS
轴突蛋白合成的调节
  • 批准号:
    8362758
  • 财政年份:
    2011
  • 资助金额:
    $ 40.74万
  • 项目类别:
KINETICS OF AXONAL PROTEIN SYNTHESIS AND RNA TRANSPORT
轴突蛋白合成和 RNA 运输的动力学
  • 批准号:
    8363796
  • 财政年份:
    2011
  • 资助金额:
    $ 40.74万
  • 项目类别:

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