Orphan nuclear receptors and mammalian development

器官或组织的发育往往依赖于涉及一系列基因连续激活的遗传控制等级。这些基因的活性指导了细胞分化事件，将一个基本上没有特化的细胞团变成了一个成熟的、有功能的器官。编码转录因子的基因在这样的发育途径中往往是关键的。核受体是受配体调节的转录因子，对激素或其他配体有反应。孤儿受体是核受体的一个特殊亚类，缺乏已知的生理配体，可能具有结构性转录功能。视黄醇相关的孤儿核受体b(RorB)由RorB基因编码，在大脑和视网膜中特异表达。视网膜中的表达模式提示了在神经发生和随后的光感受器分化阶段中的功能。然而，Rorb在视网膜中的功能仍然不清楚。因此，Rorb基因的研究为阐明孤儿核受体在特定的发育系统--视网膜中的新功能提供了机会。进度： 1.RorB基因在锥体发育中的作用。在双色哺乳动物中，视锥细胞表达对短波长(S，蓝色)或中长波长(M，绿色)光敏感的感光色素。差异调节M和S视蛋白表达的机制对色觉至关重要，但尚不完全清楚。我们的分析表明，在锥体发育过程中，rob基因诱导了S视蛋白基因。这些结果表明，S视蛋白基因在球果成熟过程中受RORB蛋白结合的直接调控。 2.正在进行的研究表明，Rorb也参与了杆状发育途径(与Anand Swaroop博士合作，NEI)。初步数据表明，这些功能与锥体中的功能不同。这些数据表明，Rorb是多功能的，在不同的视网膜细胞群中具有独立的作用。

The development of an organ or tissue often depends upon a genetic hierarchy of control involving the successive activation of a series of genes. The activity of these genes directs the cellular differentiation events that change a largely un-specialized cell mass into a mature and functioning organ. Genes encoding transcription factors are often critical in such developmental pathways. Nuclear receptors are ligand-regulated transcription factors that respond to hormones or other ligands. Orphan receptors are a special sub-class of nuclear receptors that lack known physiological ligands and may have constitutive transcriptional functions. The retinoid-related orphan nuclear receptor b (RORb), encoded by the Rorb gene, is specifically expressed in the brain and retina. The expression pattern in retina is suggestive of functions in neurogenesis and in the subsequent stages of differentiation of photoreceptors. However, the functions of Rorb in retina remain poorly defined. The study of the Rorb gene therefore offers the opportunity to elucidate novel functions for an orphan nuclear receptor in a defined developmental system, the retina. Progress: 1. The role of the Rorb gene in cone development. In dichromatic mammals, cones express opsin photopigments that are sensitive to short (S, blue) or medium-longer (M, green) wavelengths of light. The mechanisms that differentially regulate M and S opsin expression are critical for color vision but are incompletely understood. Our analysis has indicated that the Rorb gene induces the S opsin gene in cone development. The results suggest that the S opsin gene is directly regulated by binding of the RORb protein in cone maturation. 2. Ongoing studies suggest that RORb is also involved in the rod developmental pathway (collaboration with Dr Anand Swaroop, NEI). Preliminary data indicate that these functions are distinct from those in cones. The data suggest that RORb is multi-functional, having independent roles in different retinal cell populations.