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Elucidating the roles of Aurora B kinase in neurons


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Ng, JMJ 2012 , 'Elucidating the roles of Aurora B kinase in neurons', PhD thesis, University of Tasmania.

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To reveal molecular determinates that underlie the intrinsic molecular pathways within
neurons that support regeneration after injury, a DNA microarray study was performed on
axotomized neuronal clusters that were maintained in culture and free from glial and
astrocytes contamination. The microarray data indicated that post-injury regenerative
sprouting requires two distinct pathways; a cell survival response to protect against
pernicious secondary processes and a regenerative response driven by modulation of the
neuronal cytoskeleton. From the transcriptomic data, cell cycle associated aurora B kinase
(Aurkb), which was significantly up-regulated but never investigated in the context of
neurons, was identified for further work. Immunohistochemical studies revealed that Aurkb is
expressed extensively and cell-specifically in neurons of certain brain structures such as the
cortex, hippocampus and amygdala. Its elevated expression in the embryonic brain cortex as
compared to that of an adult implies that it may be involved in the process of brain
maturation. Interestingly, the changing localization of Aurkb within developing cultured
neurons and particularly its localisation outside of the nucleus at various stages of neuronal
maturation further suggests that it may have direct roles neurite outgrowth. Indeed, impairing
Aurkb activity in cultured neurons via different experimental approaches resulted in several
key neuronal deficits. Generally, neurons with inactive Aurkb were found to have either
shorter or no elaborated axons. They also possessed abnormally swollen cell bodies.
Enlargement of the cell body, independent of nucleus size, was related to a substantial
increase in microtubule mass within the area between the nucleus and axon hillock region.
Furthermore, their expanded cell bodies are bordered by several aberrant, thin, frayed and
highly disorganised neuritic processes. Next, yeast 2 hybrid identified INCENP as a binding
partner of Aurkb in neurons. Subsequent phosphoproteomics studies coupled with functional
analysis of protein associations have further revealed that inhibition of neuronal Aurkb
affected a cluster of proteins and kinases that are major players of neuronal cytoskeleton
regulation and organisation. In conclusion, this is the first comprehensive study of Aurkb in
the brain and neurons. Specifically, the phosphoproteomic, pharmacological and molecular
knockin and knockout studies provided considerable evidence that Aurkb has key roles in
neurite cytoskeleton modulation. Taken together, the work in this thesis has clearly identified
a novel and alternate cell cycle independent function of Aurkb in post-mitotic neurons.

Item Type: Thesis - PhD
Authors/Creators:Ng, JMJ
Keywords: neurite regeneration, microarray, Aurora B kinase, neurite outgrowth, neurons, brain, proteomics
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