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. Thyroid hormone administration was found to modify the timing and pattern of opsin expression in neonatal cone development in a mouse model, supporting the hypothesis that the hormonal ligand is important in modifying TRb2 activity in cone development. Additional studies tested 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 genes that may cooperate with the Thrb gene in the development of cone photoreceptors include those encoding deiodinase enzymes that could activate or inactivate thyroid hormone in the retinal target tissues at key stages in development. The findings suggest the multigenic nature of the controls that direct the development of cone photoreceptors. These studies have found that type 3 deiodinase, a thyroid hormone-inactivating enzyme, is expressed in the immature neural retina. Further genetic studies suggest that type 3 deiodinase is critical for limiting the exposure of immature cones to thyroid hormone at sensitive periods of development. The results indicate the importance of mechanisms that both augment as well as constrain thyroid hormone action on specific cell types in immature tissues.

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Xu, Xiaoliang L; Li, Zhengke; Liu, Aihong et al. (2017) SKP2 Activation by Thyroid Hormone Receptor ?2 Bypasses Rb-Dependent Proliferation in Rb-Deficient Cells. Cancer Res 77:6838-6850
Ng, Lily; Liu, Hong; St Germain, Donald L et al. (2017) Deletion of the Thyroid Hormone-Activating Type 2 Deiodinase Rescues Cone Photoreceptor Degeneration but Not Deafness in Mice Lacking Type 3 Deiodinase. Endocrinology 158:1999-2010
Bianco, Antonio C; Anderson, Grant; Forrest, Douglas et al. (2014) American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid 24:88-168
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
Swaroop, Anand; Kim, Douglas; Forrest, Douglas (2010) Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina. Nat Rev Neurosci 11:563-76
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
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
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

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