Abstract
Photoreceptors are the light-sensing neurons in the vertebrate retina. While rod photoreceptors are responsible for low-light, low-acuity vision, cone photoreceptors mediate high-acuity color vision. The presence of multiple cone subtypes, each expressing a unique opsin protein and sensitive to particular wavelengths of light, serves as the basis of color vision. Humans possess three cone subtypes (red-, green-, and blue-sensing) which express long wavelength sensitive (LWS), middle wavelength sensitive (MWS), and short wavelength sensitive (SWS) opsins, respectively. Zebrafish possess eight cone types, including LWS1 and LWS2. While much is known about transcriptional regulation in cones, more remains to be uncovered, especially the mechanism by which opsin genes located in tandem arrays are regulated. Expanding our knowledge of how gene expression in cone subtypes is regulated represents an important step in improving treatments for retinal diseases.
This dissertation begins with an overview of retinal development, emphasizing factors involved in retinal cell type patterning. In Chapter 2, I present my accepted manuscript that explores the transcriptional heterogeneity between and within the LWS cone subtypes in zebrafish beyond opsin expression. The LWS cone subtypes express the opsin genes lws1 and lws2, which are tandemly replicated opsin genes that are regulated by thyroid hormone. In Chapter 3, I introduce my unpublished manuscript in which we investigate the extent of transcriptional plasticity in zebrafish cones, determining whether gene expression remains plastic to thyroid hormone treatment in adult fish. Chapter 4 is an update on our progress in determining how thyroid hormone and retinoic acid regulate opsin expression in three-dimensional, human induced-pluripotent stem cell-derived retinal organoids. We also propose a multicomponent strategy for rigorous analysis of opsin expression in retinal organoids. Overall, the work presented here expands scientific knowledge of gene expression in cones and how it can be altered.