Martin, Clare Alice
(2019)
The role and function of microRNAs in the nervous system.
PhD thesis, University of Nottingham.
Abstract
In this thesis, novel functions for miRNAs in nervous system processes are characterised. It has been shown that miRNAs have the potential to play an important role in all aspects of the nervous system, from development and function to neurodegeneration. Reflecting on this breadth of possible roles for miRNAs, this is a thesis of two interconnected projects. Firstly, miRNAs with possible novel roles in inflammatory nociceptive processes were identified, and secondly, miRNAs with novel functions in nervous system development and function are investigated through the model system of Drosophila.
The work carried out demonstrates that miRNAs are dysregulated in the rat model of inflammatory pain, hyperalgesic priming. One miRNA, miR-138, has a distinctive expression profile that correlates with the pain behaviour. It is shown that miR-138 can potentially mediate inflammatory pain processes through direct targeting of the key inflammatory mediator MYD88. In order to investigate the molecular mechanisms of miRNA function in nociceptive processes, novel in vitro models were established. In these models, functional and molecular characteristics of sensory neuron cultures can be assessed within compartmentalised culture system, allowing a more accurate recapitulation of in vivo cellular environments.
The second part of this thesis focused first on the investigation of the effects that individual miRNAs can have on the development and function of the nervous system. The model of the Drosophila compound eye allowed for the identification of several miRNAs that can control crucial aspects of the development of these nervous system structures. One candidate miRNA which arose from this study, miR-190, was selected for further investigation. The expression pattern of miR-190 within the developing embryo of Drosophila was shown here through a modified in situ hybridisation protocol. Overexpression of miR-190 was found to cause detrimental effects in both Drosophila and mammalian neuron development, and a predicted conserved target for miR-190 which may explain this effect was identified, the transcription factor Dac/DACH1. An additional function for miR-190 was also proposed in this work in the mature nervous system. Inhibition of miR-190 in the neurons of adult Drosophila, leads to defects in the aged climbing ability and reduces lifespan of the adult. Bioinformatics analysis allowed for the proposal of a mechanism through which miR-190 exerts these effects, as predicted targets for the miRNA suggest a role in the modulation of the cholinergic system.
Overall, this work demonstrates the potential and breadth of miRNA functions in the nervous system, and characterises the role of two specific miRNAs within nociception, development, and aging. This work broadens our knowledge of the functioning of miRNAs themselves, and also of processes of the nervous system.
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