Thyroid hormone in color vision development Cone photoreceptors in the eye enable color vision, responding to different wavelengths of light according to what opsin pigments they express. Eldred et al. studied organoids that recapitulate the development of the human retina and found that differentiation of cone cells into their tuned subtypes was regulated by thyroid hormone. Cones expressing short-wavelength (S) opsin developed first, and cones expressing long- and medium-wavelength (L/M) opsin developed later. The switch toward development of L/M cones depended on thyroid hormone signaling through the nuclear thyroid hormone receptor. Science, this issue p. eaau6348 Human retinal organoids offer an opportunity to study the pathways regulating development of color vision. INTRODUCTION Cone photoreceptors in the human retina enable daytime, color, and high-acuity vision. The three subtypes of human cones are defined by the visual pigment that they express: blue-opsin (short wavelength; S), green-opsin (medium wavelength; M), or red-opsin (long wavelength; L). Mutations that affect opsin expression or function cause various forms of color blindness and retinal degeneration. RATIONALE Our current understanding of the vertebrate eye has been derived primarily from the study of model organisms. We studied the human retina to understand the developmental mechanisms that generate the mosaic of mutually exclusive cone subtypes. Specification of human cones occurs in a two-step process. First, a decision occurs between S versus L/M cone fates. If the L/M fate is chosen, a subsequent choice is made between expression of L- or M-opsin. To determine the mechanism that controls the first decision between S and L/M cone fates, we studied human retinal organoids derived from stem cells. RESULTS We found that human organoids and retinas have similar distributions, gene expression profiles, and morphologies of cone subtypes. During development, S cones are specified first, followed by L/M cones. This temporal switch from specification of S cones to generation of L/M cones is controlled by thyroid hormone (TH) signaling. In retinal organoids that lacked thyroid hormone receptor β (Thrβ), all cones developed into the S subtype. Thrβ binds with high affinity to triiodothyronine (T3), the more active form of TH, to regulate gene expression. We observed that addition of T3 early during development induced L/M fate in nearly all cones. Thus, TH signaling through Thrβ is necessary and sufficient to induce L/M cone fate and suppress S fate. TH exists largely in two states: thyroxine (T4), the most abundant circulating form of TH, and T3, which binds TH receptors with high affinity. We hypothesized that the retina itself could modulate TH levels to control subtype fates. We found that deiodinase 3 (DIO3), an enzyme that degrades both T3 and T4, was expressed early in organoid and retina development. Conversely, deiodinase 2 (DIO2), an enzyme that converts T4 to active T3, as well as TH carriers and transporters, were expressed later in development. Temporally dynamic expression of TH-degrading and -activating proteins supports a model in which the retina itself controls TH levels, ensuring low TH signaling early to specify S cones and high TH signaling later in development to produce L/M cones. CONCLUSION Studies of model organisms and human epidemiology often generate hypotheses about human biology that cannot be studied in humans. Organoids provide a system to determine the mechanisms of human development, enabling direct testing of hypotheses in developing human tissue. Our studies identify temporal regulation of TH signaling as a mechanism that controls cone subtype specification in humans. Consistent with our findings, preterm human infants with low T3 and T4 have an increased incidence of color vision defects. Moreover, our identification of a mechanism that generates one cone subtype while suppressing the other, coupled with successful transplantation and incorporation of stem cell–derived photoreceptors in mice, suggests that the promise of therapies to treat human diseases such as color blindness, retinitis pigmentosa, and macular degeneration will be achieved in the near future. Temporally regulated TH signaling specifies cone subtypes. (A) Embryonic stem cell–derived human retinal organoids [wild type (WT)] generate S and L/M cones. Blue, S-opsin; green, L/M-opsin. (B) Organoids that lack thyroid hormone receptor β (Thrβ KO) generate all S cones. (C) Early activation of TH signaling (WT + T3) specifies nearly all L/M cones. (D) TH-degrading enzymes (such as DIO3) expressed early in development lower TH and promote S fate, whereas TH-activating regulators (such as DIO2) expressed later promote L/M fate. The mechanisms underlying specification of neuronal subtypes within the human nervous system are largely unknown. The blue (S), green (M), and red (L) cones of the retina enable high-acuity daytime and color vision. To determine the mechanism that controls S versus L/M fates, we studied the differentiation of human retinal organoids. Organoids and retinas have similar distributions, expression profiles, and morphologies of cone subtypes. S cones are specified first, followed by L/M cones, and thyroid hormone signaling controls this temporal switch. Dynamic expression of thyroid hormone–degrading and –activating proteins within the retina ensures low signaling early to specify S cones and high signaling late to produce L/M cones. This work establishes organoids as a model for determining mechanisms of human development with promising utility for therapeutics and vision repair.

中文翻译：

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甲状腺激素信号指定了人视网膜类器官中的锥体亚型

色觉发展中的甲状腺激素 眼睛中的锥状光感受器可实现色觉，根据它们表达的视蛋白色素对不同波长的光作出反应。埃尔德雷德等人。研究了概括人类视网膜发育的类器官，并发现视锥细胞向其调谐亚型的分化受甲状腺激素的调节。表达短波 (S) 视蛋白的视锥细胞首先开发，表达长波和中波 (L/M) 视蛋白的视锥细胞随后开发。L/M 视锥细胞发育的转变取决于通过核甲状腺激素受体传递的甲状腺激素信号。科学，这个问题 p。eaau6348 人类视网膜类器官为研究调节色觉发育的途径提供了机会。介绍 人类视网膜中的锥形光感受器使白天、颜色、和高视力。人类视锥细胞的三种亚型由它们表达的视觉色素定义：蓝色视蛋白（短波长；S）、绿色视蛋白（中波长；M）或红色视蛋白（长波长；L）。影响视蛋白表达或功能的突变会导致各种形式的色盲和视网膜变性。基本原理我们目前对脊椎动物眼睛的理解主要来自对模式生物的研究。我们研究了人类视网膜，以了解产生互斥锥亚型马赛克的发育机制。人体锥体的规范发生在两步过程中。首先，决定发生在 S 与 L/M 锥体命运之间。如果选择了 L/M 命运，则在表达 L-或 M-视蛋白之间进行后续选择。为了确定控制 S 和 L/M 视锥细胞命运之间第一个决定的机制，我们研究了源自干细胞的人类视网膜类器官。结果我们发现人类类器官和视网膜具有相似的分布、基因表达谱和视锥亚型的形态。在开发过程中，首先指定 S 锥，然后是 L/M 锥。这种从 S 锥体规范到 L/M 锥体生成的时间转换是由甲状腺激素 (TH) 信号控制的。在缺乏甲状腺激素受体 β (Thrβ) 的视网膜类器官中，所有视锥细胞都发育为 S 亚型。Thrβ 与三碘甲腺原氨酸 (T3)（更活跃的 TH 形式）以高亲和力结合以调节基因表达。我们观察到，在发育早期添加 T3 会在几乎所有视锥细胞中诱导 L/M 命运。因此，通过 Thrβ 的 TH 信号传导对于诱导 L/M 视锥命运和抑制 S 命运是必要的和足够的。TH 主要以两种状态存在：甲状腺素 (T4)，TH 的最丰富的循环形式，以及 T3，它以高亲和力结合 TH 受体。我们假设视网膜本身可以调节 TH 水平来控制亚型命运。我们发现脱碘酶 3 (DIO3)，一种降解 T3 和 T4 的酶，在类器官和视网膜发育的早期表达。相反，脱碘酶 2 (DIO2)，一种将 T4 转化为活性 T3 的酶，以及 TH 载体和转运蛋白，在开发后期表达。TH 降解和激活蛋白的时间动态表达支持视网膜本身控制 TH 水平的模型，确保早期低 TH 信号以指定 S 锥体，并在开发后期确保高 TH 信号以产生 L/M 锥体。结论 对模式生物和人类流行病学的研究经常会产生无法在人类身上研究的关于人类生物学的假设。类器官提供了一个确定人类发育机制的系统，可以直接测试人类组织发育中的假设。我们的研究将 TH 信号的时间调节确定为控制人类锥体亚型规范的机制。与我们的研究结果一致，具有低 T3 和 T4 的早产人类婴儿的色觉缺陷发生率增加。此外，我们确定了一种产生一种锥体亚型同时抑制另一种锥体亚型的机制，再加上干细胞衍生的光感受器在小鼠中的成功移植和掺入，表明治疗色盲、视网膜色素变性和黄斑变性等人类疾病的疗法有望在不久的将来实现。时间调节的 TH 信号指定锥亚型。(A) 胚胎干细胞衍生的人类视网膜类器官 [野生型 (WT)] 产生 S 和 L/M 视锥细胞。蓝色，S-视蛋白；绿色，L/M-视蛋白。(B) 缺乏甲状腺激素受体 β (Thrβ KO) 的类器官产生所有 S 视锥细胞。(C) TH 信号 (WT + T3) 的早期激活指定了几乎所有的 L/M 视锥细胞。(D) 在发育早期表达的 TH 降解酶（如 DIO3）降低 TH 并促进 S 命运，而后来表达的 TH 激活调节剂（如 DIO2）促进 L/M 命运。人类神经系统内神经元亚型规范的潜在机制在很大程度上是未知的。蓝色(S)，绿色(M)，和红色 (L) 视网膜锥体可实现高敏锐度的白天和色觉。为了确定控制 S 与 L/M 命运的机制，我们研究了人类视网膜类器官的分化。类器官和视网膜具有相似的锥体亚型分布、表达谱和形态。首先指定 S 锥，然后是 L/M 锥，甲状腺激素信号控制这种时间转换。视网膜内甲状腺激素降解和激活蛋白的动态表达确保了早期低信号以指定 S 视锥细胞和高信号后期产生 L/M 视锥细胞。这项工作建立了类器官作为确定人类发育机制的模型，在治疗和视力修复方面具有广阔的应用前景。为了确定控制 S 与 L/M 命运的机制，我们研究了人类视网膜类器官的分化。类器官和视网膜具有相似的锥体亚型分布、表达谱和形态。首先指定 S 锥，然后是 L/M 锥，甲状腺激素信号控制这种时间转换。视网膜内甲状腺激素降解和激活蛋白的动态表达确保了早期低信号以指定 S 视锥细胞和高信号后期产生 L/M 视锥细胞。这项工作建立了类器官作为确定人类发育机制的模型，在治疗和视力修复方面具有广阔的应用前景。为了确定控制 S 与 L/M 命运的机制，我们研究了人类视网膜类器官的分化。类器官和视网膜具有相似的锥体亚型分布、表达谱和形态。首先指定 S 锥，然后是 L/M 锥，甲状腺激素信号控制这种时间转换。视网膜内甲状腺激素降解和激活蛋白的动态表达确保了早期低信号以指定 S 视锥细胞和高信号后期产生 L/M 视锥细胞。这项工作建立了类器官作为确定人类发育机制的模型，在治疗和视力修复方面具有广阔的应用前景。首先指定 S 锥，然后是 L/M 锥，甲状腺激素信号控制这种时间转换。视网膜内甲状腺激素降解和激活蛋白的动态表达确保了早期低信号以指定 S 视锥细胞和高信号后期产生 L/M 视锥细胞。这项工作建立了类器官作为确定人类发育机制的模型，在治疗和视力修复方面具有广阔的应用前景。首先指定 S 锥，然后是 L/M 锥，甲状腺激素信号控制这种时间转换。视网膜内甲状腺激素降解和激活蛋白的动态表达确保了早期低信号以指定 S 视锥细胞和高信号后期产生 L/M 视锥细胞。这项工作建立了类器官作为确定人类发育机制的模型，在治疗和视力修复方面具有广阔的应用前景。