Functions of thyroid hormone in retinal development

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

We identified 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. Cones also mediate vision in daylight conditions and are susceptible to degeneration in retinal disorders, such as cone dystrophies. Our findings indicate 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 express opsins for sensitivity to medium-longer (M, green) or short (S, blue) wavelengths of light. Humans share this basic cone system but have an adaptation for trichromatic vision with an additional, third cone type for sensitivity to long (L, red) wavelengths. The generation of cone diversity is crucial for color vision but the mechanisms remain poorly understood. We previously found that deletion of TRb2 in model systems results in loss of M opsin and loss of diversity such that all cones appear as S-type. Thus, TRb2 is critical for the generation of cone diversity. These findings suggest an intriguing link between the endocrine and visual systems and the ability to detect color. Previous studies of human thyroid disorders largely overlooked the possibility of defects in cone function. However, mutations in the human THRB gene have been associated with impaired photoreceptor function, suggesting a related role for the THRB gene in human cone differentiation. This project investigates how thyroid hormone receptors regulate cone differentiation, diversity and survival using mammalian genetic models. Understanding the factors that determine cone differentiation and survival may offer insights into the dysfunctional pathways that underlie loss of cones in retinal degeneration and disease. Our study aims include: 1. Investigation of the gene networks that underlie cone diversity. Previously, detailed insights into cone type distinctions had been 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 and will determine cone type distinctions using fine resolution RNA-sequencing and analyses of chromatin modifications. These studies address the fundamental question of the basis of cone type distinctions, using detailed genetic and genomic techniques. 2. Investigation of the gene network that is regulated by TRb2 in the generation of cone diversity. Given the central role of TRb2 in cone differentiation, we are pursuing a genomics approach to determine how the cone transcriptome is regulated by TRb2 with the goal of identifying genes that promote cone diversity. These studies employ a novel model that allows high affinity purification of TRb2 with associated chromatin from retina. Next generation sequencing identifies genomic binding sites for TRb2 to allow investigation of mechanisms of gene regulation in cone differentiation. We established a new Cre-driver model (Thrb-b2Cre) to facilitate analyses of TRb2-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, and how it modifies TRb2 activity in cone differentiation. Apart from a requirement for adequate supply of thyroid hormone in the bloodstream, we have shown that type 2 and type 3 deiodinase enzymes that activate or inactivate thyroid hormone, respectively, modify cone development and survival. We found previously that type 3 deiodinase (Dio3) protects cones from excessive exposure to T3, thus preventing loss of cones by apoptosis. Evidence indicates that type 2 deiodinase (Dio2) also modifies retinal cone function in mouse models. We have generated 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. This study offers insights into the genetic and hormonal controls that promote the differentiation and survival of cone photoreceptors. Gaining a deeper understanding of the role of TRb2 in cone differentiation is expected to advance our knowledge of how dysfunction of these processes may result in developmental or degenerative diseases of the retina.