Abstract
Glia cells are critical for the structure and function of the nervous system. In the retina, there are two major glial cell types: microglia, the tissue resident macrophage, and Müller glia, a radial glial cell. Glia are known to have significant roles in various conditions of the retina from early development and homeostasis to pathological aging and degeneration. Further, in some vertebrates, regeneration of the central nervous system occurs following acute injury, and glia are once again involved in this process. However, in these various conditions, there remain a myriad of underexplored and unresolved aspects of glial function. Microglia are appreciated as professional phagocytes, yet the role of Müller glia in phagocytic functions remains an area of ongoing investigation and discovery. On the other hand, Müller glia are known to be a source of progenitor cells during regeneration, yet the role of microglia in recovery from injury and the transition to regeneration remains an area without firm resolution. In this condition, there is much to be learned about both cell types and the implications of their function in performing a successful regeneration of lost neurons.To begin this dissertation, an introduction to the fundamental concepts presented in the remainder of the dissertation will be presented. This will include information on the glial cells and their role in phagocytosis, tissue repair and regeneration, and an introduction to redox biology. The following chapter (Chapter 2) will contain our published work uncovering novel interactions and dynamics in and between Müller glia and microglia using real-time imaging of whole zebrafish larvae in the context of phagocytosis of developmental cell death. We then pivot our focus towards the context of acute damage that is followed by tissue repair and regeneration. The first of these studies is presented in Chapter 3 and examines the effect of microglia on the redox biology and tissue health following the targeted ablation of rod photoreceptors. Chapter 4 is a continuation of this theme and focused on the regenerative outcomes, namely the proliferation of progenitor cells and the regeneration of rod photoreceptors, following acute damage in the context of microglia deficiency and altered activity of the Nfe2l2a pathway with both loss- and gain-of-function mutants. The final chapter contains thematically and scientifically relevant, yet unpublished works pertaining to the redox biology of microglia and the effects of the metronidazole-nitroreductase system in generating oxidative stress. The corpus of work presented in this dissertation reveals new aspects of glial cell biology in the development and regeneration of the retina.