Lyons, David Anthony; (2003) Neurogenesis in the zebrafish hindbrain. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis examines neurogenesis in the zebrafish hindbrain. The behaviour of neural progenitors in the intact vertebrate brain is poorly understood, chiefly because of the inaccessibility and poor optical qualities inherent in many model systems. To overcome these problems I have established the zebrafish hindbrain as a suitable system in which to study the dynamic behaviour of the progenitor cells that generate the neurons and glia of the brain. The morphology, behaviour and molecular characteristics of hindbrain progenitors are described and a rigorous quantification of neurogenesis is provided. The main focus of the thesis centres on the mode of division that neural progenitors undergo during neurogenesis. This has been established by following the progeny of single progenitors, labelled with a fluorescent dye, through multiple rounds of division in the living embryo. The development of such clones was often monitored in a transgenic embryo that expresses GFP in post mitotic neurons. This approach allowed individual cells to be followed through to their terminal mitosis and neurons to be phenotyped in the living animal and for lineage trees to be reconstructed. I have found that the vast majority of neurons are born following a division that generates two neurons and that asymmetric divisions that generate a neuron and a progenitor cell are comparatively rare. Furthermore I find that no progenitor behaves in the manner of a classic stem cell i.e. by undergoing repeated rounds of asymmetric division and find also that the plane of the progenitor cell's division relative to the ventricular zone does not correlate with the fate of daughter cells. In characterising the zebrafish neurogenic mutant, mindbomb I find, in contrast to published data, that non-neuronal cells exist throughout its development and that mature oligodendrocytes can be generated by mechanisms that do not involve Notch Delta mediated lateral inhibition. I propose a model that the progenitors that give rise to oligodendrocytes in the mutant were never competent to produce neurons and therefore that neuronal and glial lineages must diverge relatively early in development.

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