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Post-transcriptional regulation of adult central nervous system axonal regeneration by Cpeb1

Lou, Pak Kin

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Abstract

Axons of the adult mammalian central nervous system (CNS) are unable to regenerate following axonal injury. Thus, spinal cord injury (SCI) leads to devastating and permanent functional impairments, the extent of which depends on the position of the lesion. At present, our understanding of the response to axonal injury and what underlies the failure of CNS axons to regenerate is far from complete. Therefore, despite various strategies proposed and tried, a robust method to improve axon regeneration after SCI is yet to be found. Due to growing evidence highlighting the role of post-transcriptional control towards protein expression and the importance of localised protein synthesis in axon physiology, we decided to investigate the post-transcriptional regulation mechanisms that could govern the regeneration of CNS neurons.

At a very early time window following SCI, axon regrowth still occurs, but is however limited in duration and extent. This however offers a rare opportunity of learning how nature initiates a regenerative response in the CNS. In order to study the difference between the total level of RNA and the subset that is actually translated, we profiled and compared total and polysome-bound RNAs from spinal cords early after injury and naïve ones, and revealed substantial uncoupling between mRNA abundance and ribosome loading. mRNAs of genes related to nervous system development were highly reduced following injury, while still being stably loaded onto ribosomes. By analysing motifs recognised by RNA-binding proteins, it was discovered that mRNAs harbouring the cytoplasmic polyadenylation element (CPE) exhibit increased transcript abundance upon SCI relative to those that do not, and were highly enriched in nervous system development genes in both mouse and Drosophila genomes. By manipulating the expression of Cpeb1, the binding protein of CPE, we found that Cpeb1 is a positive regulator of regeneration in both mouse and Drosophila CNS neurons. In an attempt to identify the targets of Cpeb1 mediated injury response, we analysed the transcriptome of naïve and injured processes from wild-type and Cpeb1 knockout cortical neurons with RNAseq. It was found that Cpeb1 knockout processes have a much attenuated transcriptional activation-response towards injury. In particular, the Jun and Fos family of transcription factors, which are highly up-regulated upon injury in wild-type processes, failed to do so in their Cpeb1 knockout counterparts. In addition, Cpeb1 knockout was found to have an effect on alternative polyadenylation. However, the precise molecular mechanisms underlying observed changes remain a subject of future studies.

In conclusion, this study demonstrates widespread uncoupling between mRNA abundance and ribosome-loading in the injury response of CNS neurons, and identifies Cpeb1 as a conserved positive regulator of regeneration, as well as a mediator of this uncoupling effect.

Item Type: Dissertation
Supervisor: Martin-Villalba, Prof. Dr. Ana
Place of Publication: Heidelberg
Date of thesis defense: 30 May 2016
Date Deposited: 25 Oct 2016 08:07
Date: 2016
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
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