Abstract
Our sense of sight is the primary way humans interface with our surroundings. A significant portion of the human brain is devoted to detecting and processing visual stimuli. Vision is made possible by a specialized structure of the central nervous system called the retina located at the back of the eye. Color vision is made possible by specialized cells called cone photoreceptors in the outer most layer of the retina. Humans have three subtypes of cones red, green ,and blue. The subtype is determined by the expression of opsin proteins that are sensitive to specific wavelengths of light. These are short wavelength sensitive (SWS; blue), medium wavelength sensitive (MWS; green), and long wavelength sensitive (LWS; red). Enormous efforts have been made in deciphering how these cone subtypes are determined. Understanding of the regulatory processes involved in the determination of cone subtypes will provide the knowledge required to identify factors that may disrupt normal development of the visual system and may potentially provide insight into the creation of novel therapeutics designed to treat a multitude of visual disorders that specifically involve cone photoreceptors.
This body of work begins with an overview of retinal development, structure, and function. Next, I present my published work that has identified the nuclear signaling molecule thyroid hormone (TH) as an endogenous regulator of unique visual opsin genes in zebrafish called tandemly replicated opsin genes. Tandemly replicated genes are the result of a duplication event that results in two or more functionally related genes that are found next to each other in the genome and are regulated by the same upstream regulatory regions. These include the tandemly duplicated lws1/lws2 array and the tandemly quadruplicated rh2 array. Chapter 3 describes unpublished work in which I identify regions of the lws locus that are required for regulation by TH including two potential response elements that are critical for the differential regulation of lws1 vs lws2 in response to TH. Next I present incredible findings that detail the involvement of TH in the differential regulation of the tandemly duplicated LWS/MWS visual opsin array found on the X chromosome in humans. I also present preliminary findings in zebrafish that identify specific nuclear signaling receptors that contribute to the differential regulatory mechanism governing expression of the tandemly replicated visual opsin arrays. This body of work significantly expands upon our understanding of how cone subtypes are determined and the components of the regulatory mechanisms involved in making this determination.