Functions of thyroid hormone in retinal development

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

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Abstract

Thyroid hormone is critical for the development of the nervous system. Our study of thyroid hormone receptors identified a key role for a thyroid hormone receptor, TRb2, in the differentiation of cone photoreceptors, the light-sensitive cells that mediate color vision and vision in bright light or daytime conditions. Our findings indicate that cones are unexpectedly dependent on thyroid hormone for differentiation and survival. Color vision depends upon cone populations that express 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. However, the mechanisms that generate this diversity of cone types are poorly understood. We previously showed that deletion of TRb2 in mice results in loss of M opsin and loss of diversity such that all cones appear as S-type. Thus, TRb2 is critical for the diversification of cone sub-populations. These results suggest an intriguing link between the endocrine and visual systems. Previous studies of human thyroid disorders largely overlooked the possibility of defects in color vision or cone function. However, mutations in the human THRB gene have been associated with impairment of photoreceptor function, suggesting that this key role of the THRB gene in cone photoreceptors is conserved. This project investigates how thyroid hormone receptors regulate cone differentiation, diversity and survival in mammalian genetic models. Understanding the factors that determine cone differentiation and survival may offer insights into the dysfunctional processes that lead to loss of cones in retinal degeneration and disease. 1. Factors that determine TRb2 activity in cone differentiation. We have shown that the 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 ligand, thus preventing loss of cones by apoptosis. Recent evidence indicates that type 2 deiodinase (Dio2) also modifies retinal cone survival and function in mouse models. These studies aim to elucidate mechanisms that augment as well as constrain thyroid hormone action in differentiation. We have generated new Cre-driver models that allow us to monitor expression of both Dio2 and Dio3 deiodinase genes at the cellular level in retinal differentiation. 2. Investigation of downstream gene networks that are regulated by TRb2 during cone differentiation. We have derived new mammalian models using TRb2 as a unique marker for the isolation of cones during development. Previously, detailed analyses of cones had not been possible because of technical limitations presented by the scarcity of cones which represent only a small proportion of retinal cells. Isolated cones are amenable to analysis by next generation sequencing for both transcriptome and chromatin modifications under control by TRb2. To address the fundamental question of what distinguishes cone sub-populations, our studies use high resolution, single cell genomics techniques. 3. Elucidate a gene regulation network for cone diversity. Given the central role of TRb2 in determining opsin identities in cones, 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 can identify genomic binding sites for TRb2 to allow investigation of mechanisms of gene regulation by TRb2 in cone differentiation. We generated a new Credit-driver model (Thrb-b2Cre) that facilitates cone-specific chromatin analyses. This study offers insights into the genetic and hormonal controls that promote the differentiation and survival of cone photoreceptors. Further collaborative studies with Dr. David Cobrinik (Children's Hospital Los Angeles) indicate a role for TRb2 in retinoblastoma cells, which are thought to arise from cone-like precursor cells in retina. 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.