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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

批准号：
10306001
负责人：
JEFFERY L TWISS
金额：
$ 40.74万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10306001
关键词：
Address Adult Affect Affinity Alleles Appearance Axon Behavior Binding Binding Proteins Bioinformatics Biotinylation Clinical Collaborations Complex Data Dendrites Development Elements Environment FMRP Family Funding Genetic Transcription Genetic Translation Growth Heterogeneous-Nuclear Ribonucleoproteins Hippocampus (Brain)HuD antigen Impairment In Vitro Injury Knockout Mice Knowledge Link Mediating Memory Memory impairment Messenger RNA MicroRNAs Molecular Mus Natural regeneration Nerve Nerve Regeneration Nervous system structure Neuraxis Neurons Nuclear Peripheral Peripheral Nerves Peripheral nerve injury Physiological Prefrontal Cortex Protein Binding Domain Protein Biosynthesis Proteins Proteome RNA RNA Binding RNA analysis RNA-Binding Proteins RNA-Protein Interaction Recovery of Function Regenerative capacity Regulation Regulon Ribonucleoproteins Rodent Role Seizures Stimulus Testing Time Translating Translational Regulation Translations Up-Regulation Work axon growth axon injury axon regeneration base cohort exosome extracellular in vivo link protein mRNA Stability mRNA Transcript Degradation memory consolidation neuron loss neuronal cell body neurotransmission particle peripheral nerve regeneration presynaptic protein complex response response to injury stoichiometry transcriptome

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