Orphan nuclear receptors and mammalian development

孤儿核受体和哺乳动物发育

• 批准号: 7734145
• 负责人: Douglas Forrest
• 金额: $ 39.77万
• 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/7734145
• 关键词: Brain; Cells; Class; Collaborations; Color Visions; Condition; Data; Defect; Development; Event; Gene Expression; Genes; Genetic; Goals; Hormones; Lead; Ligands; Light; Mammals; Mediating; Molecular; Mus; Nuclear Orphan Receptor; Nuclear Receptors; Opsin; Organ; Orphan; Pathway interactions; Pattern; Phenotype; Photoreceptors; Physiological; Population; Proteins; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinal Diseases; Retinoids; Role; Series; Specificity; Staging; System; Tissues; Transcription factor genes; Vertebrate Photoreceptors; Vision; cell type; mouse model; neurogenesis; novel; receptor; receptor binding; research study; retinal progenitor cell; retinal rods; transcription factor

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.

器官或组织的发展通常取决于控制的遗传层次结构，涉及一系列基因的连续激活。 这些基因的活性指导细胞分化事件，这些事件将很大程度上不具体的细胞质量变为成熟且功能性的器官。 编码转录因子的基因在此类发育途径中通常至关重要。 核受体是配体调节的转录因子，对激素或其他配体有反应。 孤儿受体是缺乏已知生理配体的特殊核受体的特殊子类，可能具有组成型转录功能。 由RORB基因编码的类视黄素相关的核受体B（RORB）在大脑和视网膜中特别表达。 视网膜中的表达模式暗示了神经发生的功能以及感光体分化的后续阶段。但是，RORB在视网膜中的功能仍然很差。 因此，RORB基因的研究提供了机会，可以阐明定义的发育系统中的孤儿核受体的新功能。进步： 1。rorb基因在锥发育中的作用。 在二分性哺乳动物中，锥体表达对短的（S，蓝色）或中长（M，绿色）光的光敏感的Opsin光鲜摄影。 差异调节M和S OPSIN表达的机制对于色觉至关重要，但尚未完全理解。 我们的分析表明，RORB基因在锥发育中诱导了S OPSIN基因。 结果表明，S Opsin基因是通过锥体成熟中RORB蛋白的结合直接调节的。 2。正在进行的研究表明，Rorb也参与了Rod发育途径（与NEI的Anand Swaroop博士合作）。 初步数据表明这些功能与锥体中的功能不同。 数据表明RORB是多功能的，在不同的视网膜细胞种群中具有独立的作用。