Functions of thyroid hormone in retinal development

色觉取决于视蛋白色素在视网膜锥光感受器中的差异表达，视蛋白色素赋予对可见光谱的不同区域的敏感性。 大多数哺乳动物物种是二色性的，并表达视蛋白，对中长波长（M，绿色）或短波长（S，蓝色）的光敏感。 人类共享这个系统，但由于基因复制产生了另一个对长波（L，红色）光敏感的视蛋白基因，因此具有三色功能。 视蛋白的差异模式化机制对色觉至关重要。 然而，潜在的信号和遗传控制在很大程度上仍然难以捉摸。 我们对Thrb甲状腺激素受体基因的研究确定了甲状腺激素受体TRb2在小鼠模型中视锥细胞亚群中M和S视蛋白表达多样化中的意外关键作用。 TRb2的缺失导致M视蛋白的损失，揭示了TRb2在视蛋白图案化中的关键作用。 这一发现的意外性质引发了关于内分泌和视觉系统之间联系的问题。 以前，在人类或哺乳动物模型物种的甲状腺疾病的研究中，色觉缺陷的可能性在很大程度上被忽视了。 该项目旨在研究TRb2和甲状腺激素如何调节视锥细胞发育，并研究哪些基因可能与Thrb在彩色视觉系统中合作。 进度： 1.发现甲状腺激素给药可改变小鼠模型中新生视锥细胞发育中视蛋白表达的时间和模式，支持激素配体在视锥细胞发育中改变TRb2活性方面很重要的假设。 其他研究正在测试在视网膜发育的敏感早期阶段缺乏甲状腺激素的后果。 这些研究将表明视蛋白异常或其他锥缺陷，可能会出现在甲状腺发育障碍。 2. 可能与Thrb基因在视锥光感受器的发育中合作的候选基因包括编码脱碘酶的那些基因，所述脱碘酶可以在发育的关键阶段激活或抑制视网膜靶组织中的甲状腺激素。 这些发现表明，控制锥状光感受器发育和颜色视觉系统功能的控制具有多基因的性质。 正在进行的研究已经确定了胚胎和新生儿阶段的神经视网膜中的脱碘酶表达。 3型脱碘酶是一种甲状腺激素失活酶，在未成熟的神经视网膜中表达。遗传模型的研究表明，3型脱碘酶对于限制未成熟视锥细胞在发育敏感期暴露于甲状腺激素至关重要。 这些结果表明，在未成熟组织中，甲状腺激素对特定细胞类型的作用既可以增强也可以限制，这些机制在发育中具有重要意义。

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 are testing the consequences of a lack of thyroid hormone at sensitive, early stages of retinal development. These studies would indicate opsin abnormalities or other 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 and the function of the color visual system. Ongoing studies have identified deiodinase expression in the neural retina at embryonic and neonatal stages. Type 3 deiodinase, a thyroid hormone-inactivating enzyme, was found to be expressed in the immature neural retina. Studies in genetic models suggest type 3 deiodinase is critical for limiting the exposure of immature cones to thyroid hormone at sensitive periods of development. The results indicate the developmental importance of mechanisms that both augment as well as constrain thyroid hormone action on specific cell types in immature tissues.