Thyroid hormone receptors and development

甲状腺激素在许多组织和器官系统中介导一系列显著的功能。 这些功能在发育和成人体内平衡中都很重要。 反应的广度提出了一个关键问题，即决定甲状腺激素反应的性质、时间和地点的机制。 一种激素是如何引起如此多的不同反应的？ 甲状腺激素受体（TR）作为配体调节的转录因子，在产生细胞反应的事件链中占据关键位置。 两个受体基因，Thrb和Thra，编码几种TR亚型，表达在不同的发育和组织特异性模式。因此，在特定组织中表达给定受体同种型的能力提供了赋予特异性生物反应的手段。 该项目研究了指导由Thrb基因编码的TRb亚型的独特表达模式的机制，作为决定甲状腺激素特定功能的机制。 进度： 1. Thrb基因具有异常大和复杂的结构，在人类3号染色体或小鼠14号染色体上跨越约400 kb。 在小鼠模型品系中的详细作图研究已经鉴定了小鼠Thrb基因的控制区域，其指导TRb2同种型在垂体、耳蜗和视网膜中的组织特异性表达。 基因组DNA的高度特化控制区位于基因的非编码内含子区。 控制区的不寻常的位置和多功能的性质提供了一个具有生物学重要性的模型系统，在其中研究调节不同组织中染色质结构和基因活性的转录机制。 2. 为了研究这些染色体控制区域在人类中的意义，将小鼠Thrb基因的内含子和启动子区域与人THRB基因的相应区域进行了比较。这些序列中多态性变化在人类甲状腺激素抵抗疾病中的潜在作用正在从患者的一系列DNA样本中进行研究（与F。Celi，NIDDK）。

Thyroid hormone mediates a remarkable range of functions in many tissues and organ systems. These functions are important both in development and adult homeostasis. The breadth of responses raises a key question concerning the mechanisms that determine the nature, time and place of a given response to thyroid hormone. How does one hormone elicit so many different responses? Thyroid hormone receptors (TR) act as ligand-regulated transcription factors and occupy a key position in the chain of events that produce the cellular response. Two receptor genes, Thrb and Thra, encode several TR isoforms that are expressed in different developmental and tissue-specific patterns. Thus, the ability to express a given receptor isoform in a particular tissue provides a means of conferring a specific biological response. This project investigates the mechanisms that direct the unique expression patterns of the TRb isoforms encoded by the Thrb gene as a mechanism that determines specific functions of thyroid hormone. Progress: 1. The Thrb gene has an unusually large and complex structure, spanning about 400 kb on human chromosome 3 or mouse chromosome 14. A detailed mapping study in mouse model strains, has identified control regions of the mouse Thrb gene that direct tissue-specific expression of the TRb2 isoform in pituitary, cochlea and retina. This highly specialized control region of genomic DNA lies in a non-coding, intron region of the gene. The unusual location and multi-functional nature of the control region provides a model system of biological importance in which to investigate the transcriptional mechanisms that regulate chromatin structure and gene activity in different tissues. 2. To investigate the significance of these chromosomal control regions in humans, the intron and promoter regions of the mouse Thrb gene have been compared with the corresponding regions of the human THRB gene. The potential role of polymorphic changes in these sequences in the human disease of resistance to thyroid hormone is being investigated in a series of DNA samples from patients (collaboration with Dr F. Celi, NIDDK).