Genes that mediate thyroid hormone actions

甲状腺激素在脊椎动物的发育和生理中具有多种功能。在人类中，发育中的甲状腺激素异常会导致智力和身体发育迟缓。成年期的异常会导致一系列不同的缺陷。一个根本性的问题是这种荷尔蒙如何实现其多重功能。甲状腺激素受体控制着荷尔蒙信号转化为细胞反应的关键点。作为核受体家族的成员，TRs作为配体调节的转录因子发挥作用。我们的研究解决了Thrb和ThrA基因编码的TRs的作用。这些基因各自起什么作用？它们如何在不同的组织中调节特定的功能？靶向突变已经揭示了内分泌功能、生长和发育的作用，包括在听觉和色觉的感觉系统中重要的、在某些情况下意想不到的作用。我们试图阐明甲状腺激素作用的机制，并揭示这种激素的新功能。 除了受体，甲状腺激素的作用还在其他关键步骤中确定。因此，人们期望其他基因与tr基因协同工作。一个例子是脱碘酶激活或失活荷尔蒙，这可能在一些目标组织中施加强大的控制水平。我们的研究旨在了解调节甲状腺激素在哪里、何时和如何起作用的各种机制。 1.彩色视觉系统的开发。视锥感光细胞是调节颜色知觉的感觉细胞，这是通过表达对可见光光谱不同区域(啮齿动物的蓝色和绿色)敏感的视蛋白光色素来实现的。锥体光感受器的产生和分化以及它们表达的视蛋白的选择都是鲜为人知的过程。我们发现，甲状腺激素受体(TRb2)对于未成熟球果分化为蓝色和绿色亚型是必不可少的。有证据表明，锥体在默认情况下会获得蓝色标识，而TRb2会将一个子种群切换为绿色。最近的发现包括甲状腺激素配体本身在抑制或限制未成熟视锥细胞蓝视蛋白表达方面的作用的证据。 2.甲状腺激素与听力。听觉系统提供了另一个新的但更复杂的重要甲状腺激素作用的例子。人类先天性甲状腺激素缺陷与耳聋有关，尽管这种激素在这个系统中是如何作用的还没有很好的定义。甲状腺激素受体，特别是Thrb基因编码的甲状腺激素受体，在耳蜗生后分化和功能启动的后期参与了许多事件，涉及感觉毛细胞和其他类型的细胞。最近的研究包括一项关于Thra受体基因在听力中的作用以及可能导致耳聋的突变的调查。 3.脱碘酶与TRs的协同作用。识别改变甲状腺激素受体功能的基因应该有助于深入了解甲状腺激素的组织特异性功能是如何定义的。激活或灭活激素的脱碘酶是可以对TR活性施加强大的、组织特异性控制的候选酶。与V.Galton博士合作(达特茅斯医学。有证据表明，2型脱碘酶是一种甲状腺激素激活酶，对听力至关重要。最近的研究结果也表明，3型脱碘酶，一种激素失活酶，在听力发育中起着至关重要的作用。3型脱碘酶在视锥感光细胞的发育过程中也起着关键作用。 4.在更广泛的背景下，TR基因可能与其他类型的基因协同作用，指导不同系统的发育。候选对象包括其他类型的核受体。有证据表明，孤儿核受体Rorb(维甲酸相关的孤儿受体b)参与了视网膜光感受器的发育。与TRs不同的是，Rorb没有已知的生理配体，它对靶基因的转录起结构性调节作用。ROB在视网膜神经发生、光感受器发育中起一定作用。

Thyroid hormone has numerous functions in development and physiology in vertebrate species. In humans, thyroid hormone abnormalities in development result in mental and physical retardation. Abnormalities in adulthood result in a different range of defects. A fundamental question concerns how this hormone achieves its multiple functions. Thyroid hormone receptors (TR) control a key point at which the hormonal signal is converted into a cellular response. As members of the nuclear receptor family, TRs act as ligand-regulated transcription factors. Our research has addressed the roles of TRs encoded by the Thrb and Thra genes. What do these genes each do and how do they mediate specialized functions in different tissues? Targeted mutagenesis has revealed roles in endocrine function, growth and development, including important and in some cases unexpected roles in the sensory systems for hearing and color vision. We seek to elucidate the mechanisms underlying thyroid hormone actions and to uncover novel functions for this hormone. In addition to the receptors, the actions of thyroid hormone are determined at other key steps. It is therefore expected that other genes cooperate with TR genes. An example is the activation or inactivation of the hormone by deiodinase enzymes, which may exert a powerful level of control in some target tissues. Our studies aim to understand the varied mechanisms that regulate where, when and how thyroid hormone acts. 1. Development of the color visual system. Cone photoreceptors are the sensory cells that mediate color perception, which is achieved by the expression of opsin photopigments with sensitivity to different regions of the visible light spectrum (blue and green in rodents). The generation and differentiation of cone photoreceptors and the choice of which opsin they express are poorly understood processes. We found that a thyroid hormone receptor (TRb2) is essential for the diversification of immature cones into blue and green sub-types. Evidence suggests that cones acquire a blue identity by default and that TRb2 switches a sub-population to become green. Recent findings include evidence for the role of thyroid hormone ligand itself in suppressing or limiting blue opsin expression in immature cones. 2. Thyroid hormone and hearing. The auditory system provides another novel but more complex example of important thyroid hormone actions. Congenital thyroid hormone defects in humans are associated with deafness, although it is not well defined how the hormone acts in this system. Thyroid hormone receptors, especially, those encoded by the Thrb gene contribute to many events in the later stages of postnatal differentiation and onset of function of the cochlea, involving the sensory hair cells and other cell types. Recent studies include an investigation of the role of the Thra receptor gene in hearing and of mutations that may cause deafness. 3. Cooperation of deiodinases and TRs. The identification of genes that modify TR functions should yield insights into how the tissue-specific functions of thyroid hormone are defined. Deiodinase enzymes that activate or inactivate the hormone are candidates that could exert powerful, tissue-specific control over TR activity. In collaboration with Dr. V. Galton (Dartmouth Med. School), evidence suggests that type 2 deiodinase, a thyroid hormone-activating enzyme, is critical for hearing. Recent results also indicate an essential role for type 3 deiodinase, a hormone-inactivating enzyme, in the development of hearing. Type 3 deiodinase also has a critical role in the development of cone photoreceptors. 4. In the broader context, the TR genes may cooperate with other types of gene in directing the development of different systems. Candidates include other types of nuclear receptor. Evidence indicates that the orphan nuclear receptor RORb (retinoid-related orphan receptor b) is involved in retinal photoreceptor development. Unlike TRs, there is no known physiological ligand for RORb, which acts constitutively to regulate transcription of target genes. RORb has some role in retinal neurogenesis photoreceptor development.