Florey Department of Neuroscience and Mental Health - Theses
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ItemInvestigating the role of Tyro3 in the central nervous system( 2020)One of the more remarkable aspects of myelination is the relationship between axon diameter and the correlating myelin thickness, whereby larger axons are ensheathed with more myelin. However, key regulators of myelin thickness in the CNS remain elusive. Previously, it was shown that that the tyrosine kinase receptor, Tyro3, is a key mechanistic component involved in controlling myelin thickness in the optic nerves of adult mice. Moreover, provision of the Tyro3 ligand, Gas6, dramatically increases clinical outcomes in a demyelinating mouse model. Tyro3 ligand provision also increased the corresponding total amount of myelin produced by myelinating oligodendrocytes in vitro. In addition, the promyelinating effects of Gas6 in vitro were lost when oligodendrocytes were devoid of Tyro3, suggesting the myelinating effect of Gas6 is up oligodendrocytes and is mediated by Tyro3. This thesis aims to further investigate the myelin regulatory role of Tyro3, firstly by assessing myelin thickness and oligodendrocyte maturation in a separate white matter tract in adult mice, the corpus callosum. Furthermore, this study aims to investigate the role of Tyro3 in demyelination and remyelination using the cuprizone induced, demyelinating mouse model. In addition, this study looks to identify the intracellular pathways in which Tyro3 and Gas6 regulate myelination in mouse oligodendrocytes. Finally, this study aims to understand how a nervous system devoid of Tyro3 functions by investigating action potential conduction in visual evoked potentials and compound action potentials. This research project shows that Tyro3 is a critical regulator of adult mouse myelin thickness, and that its expression is protective during demyelination and acts as a positive regulator of remyelination in the corpus callosum. Importantly, hypomyelination in the absence of Tyro3 occurred without alterations to oligodendrocyte maturation or mature oligodendrocyte density during the myelin establishment processes. In addition, although demyelination was more severe in the Tyro3 KO mice, microglial activation was normal. However, I was unable to identify an intracellular pathway in which Gas6 and Tyro3 may regulate myelin synthesis in mouse oligodendrocytes. Furthermore, the previously reported, promyelinating effects of Gas6 was not recapitulated when oligodendrocytes were grown on synthetic nanofibers rather than live neurons. These results suggest that the promyelinating effects of Gas6 could potentially be indirect and through neurons. Moreover, this study finds that in the absence of Tyro3, myelin loop arrangement at the node of Ranvier is significantly more disrupted than that of WT mice. However, the hypomyelinated and abnormal paranodal loop phenotype of the Tyro3 KO mice did not alter action potential conduction in the optic nerve or corpus callosum. To expand upon this, when the myelin structural parameters of Tyro3 deficient mice were placed within a synthetic action potential conduction model, a significant decrease in conduction velocities was observed in a single axon; however, it was lost when 400 axons were modelled as a myelinated tract. Finally, I show that in the absence of Tyro3, retinal function is significantly decreased, with fewer retinal ganglion cells present and a significant decrease in retinal ganglion cell dendritic density.