Functions of thyroid hormone in retinal development

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

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Abstract

We found an unexpectedly critical role for a thyroid hormone receptor, TRb2, encoded by the THRB gene, in the differentiation of cone photoreceptors, the light-sensitive cells that mediate color vision. This was unexpected because thyroid dysfunction was not traditionally associated with retinal disorders. Cones mediate color vision and also high acuity vision in daylight conditions. Cone defects are associated with disorders such as cone dystrophies, macular dystrophy or retinal degeneration. We found that cones are surprisingly dependent on thyroid hormone for differentiation and survival. Color vision requires cone populations with opsin photopigments for response to different regions of the light spectrum. Most mammalian species are dichromatic and differentially express two opsins for sensitivity to medium-longer (M, green) or short (S, blue) wavelengths of light. Humans share this cone system but possess trichromatic vision conferred by an additional, third cone type for sensitivity to long (L, red) wavelengths. The generation of different cone types is crucial for color vision but the mechanisms are poorly understood. Deletion of TRb2 in mammalian model systems results in loss of M opsin and an outcome whereby all cones are S-type. These findings suggest an intriguing link between the endocrine and visual systems. Previous studies of human thyroid disorders tended to overlook the possibility of retinal defects. However, some, rare mutations in the human THRB gene have been associated with retinal defects, suggesting a related role for the THRB gene in human retina. This project investigates how thyroid hormone regulates cone differentiation using mammalian genetic models. Understanding the basis of cone differentiation and survival may offer insights into causes of cone dystrophy or retinal degeneration. The project themes involve neuroscience, as well as genetics and genomics approaches. The aims include: 1. Investigation of the gene networks that underlie the generation of different cone types. Previously, insights into cone type distinctions were hindered because of technical limitations and the scarcity of cones which represent only a small proportion of retinal cells. We take advantage of model systems for the isolation of cones, followed by RNA-sequencing and analyses of chromatin modifications. These studies address the question of cone type distinctions using detailed genetic and genomic techniques. 2. Investigation of the TRb2-regulated gene network in the generation of different cone types. Given the central role of TRb2 in cone differentiation, we are investigating the TRb2-regulated transcriptome to identify genes that promote cone distinctions. We also employ new genetic tag models to purify TRb2-associated chromatin from retina, followed by next generation sequencing to indicate genomic binding sites for TRb2 and mechanisms of gene regulation in cone differentiation. We derived new Cre-driver models (Thrb-b2Cre and Thrb-b1Cre) to facilitate analyses of TR-regulated chromatin in the retina. 3. Factors that modify TRb2 activity in cone differentiation. An important question concerns the role of T3, the primary active form of thyroid hormone, in modifying TRb2 activity in cone development. Apart from adequate thyroid hormone in the bloodstream, we found that type 2 and type 3 deiodinase enzymes that activate or inactivate thyroid hormone, respectively, within the retina, modify cone development. Type 3 deiodinase (Dio3) protects cones from excessive exposure to T3, thus preventing loss of cones by apoptosis and type 2 deiodinase (Dio2) also modifies cone function in genetic models. We have derived new Cre-driver models that allow us to monitor expression of both Dio2 and Dio3 deiodinase genes at the fine cellular level and investgate genomic regulation in specific cell types in retinal differentiation. We also found that a membrane transporter for thyroid hormone is necessary for the control of opsin expression during cone differentiation. This project offers insights into genetic and hormonal controls that promote the differentiation and survival of cone photoreceptors. Gaining a deeper understanding of cone differentiation is expected to advance our knowledge of how cone dysfunction may result in developmental or degenerative diseases of the retina.