Color vision depends upon the differential expression in retinal cone photoreceptors of opsin photopigments that confer sensitivity to different regions of the visible 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 system but have trichromatic function because of a gene duplication that created another opsin gene for sensitivity to long wave (L, red) light. The mechanisms that differentially pattern opsins are critically important for color vision. However, the underlying signals and genetic controls have remained largely elusive. Our study of the Thrb thyroid hormone receptor gene identified an unexpectedly critical role for a thyroid hormone receptor, TRb2, in the diversification of M and S opsin expression in sub-populations of cones in a mouse model. Deletion of TRb2 results in a loss of M opsin, revealing a key role for TRb2 in opsin patterning. The unexpected nature of this finding raises questions regarding the link between the endocrine and visual systems. Previously, in the study of thyroid disorders in humans or in mammalian model species, the possibility of color visual deficiencies had been largely overlooked. The project aims to investigate how TRb2 and thyroid hormone regulate cone development and to investigate which genes may cooperate with Thrb in the color visual system. Progress: 1. The role of thyroid hormone in modifying the timing and pattern of opsin expression in cone development in a mouse model. We continue to investigate this key question to test the hypothesis that TRb2 and the hormonal ligand is important in modifying cone development, function and survival. In additional studies, we continue to test the consequences of a lack of thyroid hormone at sensitive, early stages of retinal development to indicate possible cone defects that may potentially arise in developmental thyroid disorders. 2. Candidate factors that may cooperate with TRb2 in the development of cone photoreceptors include other transcription factors and at the pre-receptor stage, the deiodinase enzymes that could activate or inactivate thyroid hormone in the retinal target tissues at key stages in development. We continue to investigate the multigenic nature of the controls that direct the development of cone photoreceptors. These studies investigate the importance of mechanisms that both augment as well as constrain thyroid hormone action in the differentiation of specific cell types in immature tissues. 3. Investigation of the target genes that are regulated by TRb2 in retinal development. We continue our studies to identify the downstream genes that mediate thyroid hormone action in the retina. The identification of these critical target genes is expected to reveal insights into mechanisms of action of thyroid hormone and to identify new genes involved in photoreceptor differentiation and potentially also genes that underlie developmental or degenerative diseases of the retina.

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2013
Total Cost
$395,449
Indirect Cost
City
State
Country
Zip Code
Chen, D; Chen, Y; Forrest, D et al. (2013) E2f2 induces cone photoreceptor apoptosis independent of E2f1 and E2f3. Cell Death Differ 20:931-40
Ng, Lily; Lu, Ailing; Swaroop, Alok et al. (2011) Two transcription factors can direct three photoreceptor outcomes from rod precursor cells in mouse retinal development. J Neurosci 31:11118-25
Ng, Lily; Lyubarsky, Arkady; Nikonov, Sergei S et al. (2010) Type 3 deiodinase, a thyroid-hormone-inactivating enzyme, controls survival and maturation of cone photoreceptors. J Neurosci 30:3347-57
Xu, Xiaoliang L; Fang, Yuqiang; Lee, Thomas C et al. (2009) Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling. Cell 137:1018-31
Ng, Lily; Ma, Michelle; Curran, Tom et al. (2009) Developmental expression of thyroid hormone receptor beta2 protein in cone photoreceptors in the mouse. Neuroreport 20:627-31
Lu, Ailing; Ng, Lily; Ma, Michelle et al. (2009) Retarded developmental expression and patterning of retinal cone opsins in hypothyroid mice. Endocrinology 150:1536-44
Liu, Hong; Etter, Paige; Hayes, Susan et al. (2008) NeuroD1 regulates expression of thyroid hormone receptor 2 and cone opsins in the developing mouse retina. J Neurosci 28:749-56