MECHANISMS GOVERNING SPECIFICATION OF PHOTORECEPTORS IN THE MAMMALIAN RETINA
Eldred, Kiara C
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Human vision begins with detection of light by photoreceptors (PRs) in the retina, a thin layer of cells at the back of the eye. Cones are the primary daytime and color-detecting PRs that distinguish red, green, or blue light. These cells differentiate into three subtypes through a poorly understood two-step process: first, naïve PRs decide between blue and red/green fates, then between red and green fates. Despite decades of study, we know very little about the molecular mechanisms that generate cones in the human eye. This thesis describes the findings that retinal organoids recapitulate human cone specification in developmental timing, gene expression, and morphology. A temporal switch in PR development was observed where blue cones are specified first, followed by red/green cones. Moreover, this regulation is controlled by thyroid hormone (TH) signaling, which is necessary and sufficient to control cone subtype fates through the nuclear hormone receptor thyroid hormone receptor β (Thrβ). Expression of TH–regulating genes suggests that retina-intrinsic temporal control of TH levels and activity governs cone subtype specification. Interestingly, dysregulation of TH in premature infants is associated with color-vision defects, consistent with these findings. This work establishes human retinal organoids as a model system to study mechanisms of cell fate specification in developing human tissue (Eldred et al., Science, 2018). Despite years of study, the mosaic of cone cell arrangement within the entire human retina has not yet been characterized. To develop the tools necessary to image and analyze this large tissue, in this thesis we quantitatively characterized the distribution of PRs in the mouse retina. We then modeled their generation based on interactions between Thrβ and TH gradients (Eldred et al., under review PLOS Computational Biology). These studies provide a detailed map of cone subtype patterning in the mouse retina, and suggest mechanisms for its development and maintenance. These software and analysis tools will be applied to the human retina to provide the first map of human cones.