Functions of thyroid hormone in retinal development

甲状腺激素在视网膜发育中的作用

• 批准号: 9356115
• 负责人: Douglas Forrest
• 金额: $ 58.94万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9356115
• 关键词: Affinity Chromatography; Apoptosis; Apoptotic; Binding Sites; Biological; Cell Death; Cells; Chromatin; Color Visions; Cone; Data; Defect; Degenerative Disorder; Development; Endocrine system; Enzymes; Exposure to; Functional disorder; Gene Duplication; Gene Targeting; Genes; Genetic; Genomic approach; Genomics; Goals; Hormonal; Human; Investigation; Iodide Peroxidase; Knowledge; Ligands; Light; Link; Mediating; Modeling; Mus; Opsin; Outcome; Pattern; Photoreceptors; Population; Process; Protein Isoforms; Regulation; Retina; Retinal; Retinal Cone; Role; Sequence Analysis; Signal Transduction; Staging; Stem cells; System; Testing; Thyroid Diseases; Thyroid Hormone Receptor; Thyroid Hormones; Tissues; Visible Radiation; Vision; Visual system structure; cell type; cofactor; differential expression; genetic approach; insight; nervous system development; next generation sequencing; novel; prevent; receptor; response; transcriptome

Thyroid hormone is well-known as an important factor for the development of the nervous system. Our study of the thyroid hormone receptor b gene (Thrb) identified a key role for a thyroid hormone receptor, TRb2, in the differentiation of retinal cone photoreceptors, the light-sensitive cells that mediate vision in bright light and color vision. The findings indicate that, unexpectedly, the retina is an unexpectedly sensitive target of thyroid hormone. Color vision depends upon the differential expression in cone photoreceptors of opsin photopigments for response 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 the presence of third opsin gene for sensitivity to long wave (L, red) light. The mechanisms that pattern opsins are central for color vision but the underlying controls remain largely elusive. Our study showed that deletion of TRb2 results in loss of M opsin and therefore revealed that TRb2 is critical for the diversification of M and S cone sub-populations in mice. This unexpectedly critical finding raises intriguing questions about a functional link between the endocrine and visual systems. Previously, studies of human thyroid disorders largely overlooked the possibility of defects in color vision or in photoreceptor function. This project investigates how TRb2 regulates cone differentiation and long term survival. Progress: 1. Candidate factors that cooperate with TRb2 in the development of cone photoreceptors include the type 2 and type 3 deiodinase enzymes that activate or inactivate thyroid hormone, respectively, in tissues at key stages in development. Previous studies indicated that type 3 deiodinase protects cones from excessive exposure to ligand, thus preventing loss of cones by apoptosis. We are also investigating the role of type 2 deiodinase in retinal development. These studies investigate the importance of mechanisms that augment as well as constrain thyroid hormone action in the differentiation of specific cell types during development. 2. Investigation of genes that are regulated by TRb2 during cone differentiation. We are using a new model that allows marking and isolation of cones throughout development. Previously, detailed analyses of cones have not been possible because of the technical limitations that cones are scarce (and represent only 3% of retinal cells in mice) and beause of the lack of a specific marker for isolating immature cones at early stages. Isolated cones are amenable to analysis by next generation sequencing and our approach has yielded high quality transcriptome data for cones. Ongoing studies comparing the transcriptome of TRb2-deficient and control cones, will reveal candidate target genes for TRb2. 3. Investigation of genes that are direct targets of TRb2. We continue to pursue this goal using a new model that allows high affinity purification of TRb2 with associated chromatin from retina. Next generation sequencing analysis identifies genomic binding sites that suggest novel target genes for TRb2. In summary, our study offers new insights into the genetic and hormonal controls that promote the differentiation of cone photoreceptors. Understanding these processes underlying the differentiation and survival of cones is also expected to advance our knowledge of how dysfunction of these processes may result in developmental or degenerative diseases of the retina.

甲状腺激素众所周知是神经系统发展的重要因素。 我们对甲状腺激素受体B基因（THRB）的研究确定了甲状腺激素受体TRB2在视网膜锥光受体分化中的关键作用，这是视网膜光感受器的分化，这是在明亮的光线和彩色视觉中介导视觉的光敏感细胞。研究结果表明，意外的是视网膜是甲状腺激素的意外敏感靶标。 彩色视觉取决于Opsin Phopopigments锥光受体中的差异表达，以响应可见光光谱的不同区域。大多数哺乳动物物种都是二分和表达蛋白，以敏感到中等长度（M，绿色）或短（S，蓝色）光的光长度。人类共享该系统，但具有三色功能，因为存在第三个OPSIN基因以敏感长波（L，红色）光。模式OPSIN的机制对于色觉是核心，但基本的控制措施在很大程度上仍然难以捉摸。我们的研究表明，TRB2的缺失会导致M opsin的丧失，因此表明TRB2对于小鼠M和S锥子群的多样化至关重要。 这一出乎意料的关键发现引发了有关内分泌和视觉系统之间功能联系的有趣问题。以前，对人甲状腺疾病的研究在很大程度上忽略了色觉或感光体功能中缺陷的可能性。该项目研究了TRB2如何调节锥体分化和长期存活。 进步： 1。在锥形光感受器开发中与TRB2合作的候选因子包括2型和3型去二十二酶酶，分别激活或灭活甲状腺激素，在发育中关键阶段的组织中。 先前的研究表明，3型脱碘酶可保护锥体免受配体的过度暴露，从而防止凋亡因凋亡而失去锥体。 我们还正在研究2型去二二酶在视网膜发育中的作用。这些研究研究了在发育过程中特定细胞类型的分化中增强和限制甲状腺激素作用的机制的重要性。 2。研究锥体分化过程中受TRB2调控的基因。 我们正在使用一个新模型，该模型允许在整个开发过程中标记和隔离锥体。 以前，由于锥体稀缺（仅代表小鼠中仅3％的视网膜细胞）和缺乏特定标记以在早期阶段隔离未成熟锥的特定标记的技术局限性，因此无法对锥体进行详细分析。 隔离锥可通过下一代测序对分析进行分析，我们的方法产生了锥体的高质量转录组数据。 正在进行的研究比较TRB2缺陷型和对照锥的转录组，将揭示TRB2的候选靶基因。 3。研究是TRB2的直接靶标的基因。 我们继续使用新模型来追求这一目标，该模型允许将TRB2与视网膜相关的染色质进行高亲和力净化。 下一代测序分析确定了建议TRB2的新靶基因的基因组结合位点。 总而言之，我们的研究为促进锥形感光体分化的遗传和激素对照提供了新的见解。 还希望了解锥体分化和生存的基础的这些过程，还可以提高我们对这些过程功能障碍如何导致视网膜发育或退化性疾病的了解。