The role of intrinsic versus extrinsic cues during zebrafish retinal development and regeneration

During retinal neurogenesis, the main regulators of cell fate specification are genes (intrinsic). Recently, studies have challenged this notion, and accumulating evidence suggests that environmental (extrinsic) cues also contribute to retinal development. However, how these extrinsic factors influence different aspects of retinal development remains largely unknown. In this thesis I show that intrinsic factors control the timing of cell cycle exit in an environment with reduced inhibitory neurons compared to a wild type environment. This first study was consistent with the status quo of cell cycle exit being primarily regulated intrinsically during development. However, I also show that fate specification of later born neurons is delayed in an environment missing a single neuron type. Thus, indicating that later born cells rely on feedback from the surrounding environment to determine fate choice. This observation expands our understanding of retinal development and may be able to progress research in therapeutic regeneration for developmental diseases through extrinsically regulating cell fate, such as in the area of cell transplantation therapy. In response to injury in vertebrate retinas, different types of growth and cell signalling factors are produced. These factors have been tested in vivo and have been shown to improve regeneration in a number of different injury models (i.e. exposure to bright light, mechanical and chemical injury). However, the relative contribution of extrinsic factors and their influences on different aspects of regeneration such as on fate specification is largely unknown. In this thesis, my data show that an environment created from an injury that ablates only one neuron type will generate larger proportions of the missing neuron. This implies that there are environmental factors that are able to direct fate choice of progenitor cells after an injury. Thus, this provides a platform to progress regenerative therapies for retinal diseases. For example, transplanting unspecified progenitors into the retina of a patient to selectively generate the missing neurons.