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Deciphering the role of Aurora kinase B in neurite outgrowth and axon regeneration

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thesis
posted on 28.03.2022, 12:43 authored by Sze Ling Serene Gwee
Neurons in the adult central nervous system generally do not regenerate following injury or disease, partly due to the inhibitory molecular and cellular environment surrounding the injured neurons. Previous observations using isolated neuronal cultures suggested that neurons have an innate ability to regenerate from injury. Current strategies are focused in reducing the inhibitory extracellular environment and boosting the endogenous regenerative signalling pathways within injured neurons to promote neural regeneration.Following experimental axonal transection of cultured neurons, a recent transcriptomic study has revealed that the most highly upregulated mRNA during the regenerative response of injured neurons encodes for the expression of a serine/threonine protein kinase, Aurora kinase B (AurkB). While this suggests that AurkB might be involved in axonal regeneration, the molecular mechanisms in which AurkB mediates axonal regeneration are still not clear.This PhD aims to evaluate the molecular role of AurkB in developing and regenerating neurons and to identify the signalling pathways regulated by AurkB to promote neuronal outgrowth and regeneration. These were investigated using complementary in vitro cell culture and in vivo zebrafish models of neuronal development and injury.In both cell culture and zebrafish models, manipulating either the expression or the kinase activity of AurkB resulted in altered axonal growth, confirming the involvement of AurkB in this process. Using quantitative phosphoproteomic profiling, several possible substrates of AurkB were identified and similarly described in the literature to be involved in the neurite outgrowth process. Subsequent pathway analysis with Ingenuity Pathway Analysis software identified a novel AurkB-mediated axonal outgrowth pathway. A new experimental model of axonal regeneration was also developed where the axon of a single spinal motor neuron is severed in living zebrafish. With this model, pharmacological inhibition of AurkB activity was observed to impede axonal regeneration. Collectively, this thesis presents compelling complementary streams of evidence suggesting that AurkB contributes to the regulation of neuronal development and regeneration following axonal injury.

History

Table of Contents

Chapter 1 - Literature review -- Chapter 2 - Aurora kinase B regulates in vitro axonal outgrowth through a C-Raf/ERK-mediated pathway and regulation of microtubule dynamics -- Chapter 3 - Aurora kinase B regulates axonal development and regeneration of zebrafish spinal motor neurons -- Chapter 4 - Creation and initial characterisation of stable transgenic zebrafish with motor neuron-specific overexpression of Aurkb -- Chapter 5 - Conclusions and future directions

Notes

Bibliography: pages 295-348 Theoretical thesis.

Awarding Institution

Macquarie University

Degree Type

Thesis PhD

Degree

PhD, Macquarie University, Faculty of Medicine and Health Sciences, Department of Biomedical Sciences

Department, Centre or School

Department of Biomedical Sciences

Year of Award

2017

Principal Supervisor

Roger Chung

Additional Supervisor 1

Albert Lee

Rights

Copyright Gwee Sze Ling Serene 2017 Copyright disclaimer: http://mq.edu.au/library/copyright

Language

English

Extent

1 online resource (xxi, 359 pages) illustrations

Former Identifiers

mq:72008 http://hdl.handle.net/1959.14/1280479