Nuclear Receptor and Co-Repressor Function in Eye Development

核受体复合物长期以来被称为配体激活的转录因子。 最近的细胞培养工作有力地表明，核受体二聚体可以对单个启动子起负作用，也可以起正作用。 核受体介导的阻遏依赖于核受体辅阻遏物，其结合无配体的核受体二聚体。 这些co-repressors被取代配体，消除镇压，并允许激活因子bind. To研究在体内的核受体和他们的co-repressor合作伙伴的作用，实验将检查的作用，RXR-含有二聚体的细胞命运的调节，分化和协调的发展，使用果蝇眼睛作为一个实验上可行的系统。 为了使遗传，发育和分子的方法来解决这个问题，在正常的发展，实验集中在超气门（USP），果蝇RXR，在控制形态发生沟运动和细胞分化的最早阶段在eye.The发展中的果蝇眼睛提供了一个很好的模型，研究RXR介导的激活/抑制系统的作用。 眼原基的特征是有一个明显的收缩，即形态发生沟，将眼的后部和前部分开。 形态发生沟由后向前穿过原基。 前区的细胞是未分化的，没有任何特定的命运。 形态发生沟的正常运动和形态发生沟后的正常分化需要超气门的作用。 在没有超气门的情况下，犁沟比正常情况下移动得更快，后部的细胞定型发生得更快。 这些表型表明抑制由ultraspicle-containing二聚体和两个救济的阻遏和激活附近或内的形态发生沟的可能性。 一个候选的辅阻遏物在眼睛中表达，工作将针对usp，它的二聚体伴侣和辅阻遏物伴侣在控制犁沟运动和犁沟后分化中的作用。 实验将测试usp的前沟和后沟功能的独立性，以及具体解决前抑制的机制和配体诱导的形态发生沟内激活的可能性和机制。 最有可能的核受体伴侣的抑制和激活usp将测试在这个系统中使用在体外产生的显性突变的功能。在果蝇眼睛发育和哺乳动物的肢体，心脏，眼睛和神经系统的调节系统之间的高度相似性，使其极有可能，这些研究的结果将深入了解在其他生物体的多个过程。

Nuclear receptor complexes have long been known as ligand-activated transcription factors. Recent cell culture work strongly suggests that nuclear receptor dimers can act negatively as well as positively on a single promoter. Nuclear receptor-mediated repression depends on nuclear receptor co-repressors which bind to ligand free nuclear receptor dimers. These co-repressors are displaced by ligand, removing repression, and allowing activating factors to bind.In order to study the in vivo role of nuclear receptors and their co-repressor partners, experiments will examine the role of RXR-containing dimers in the regulation of cell fate, differentiation and the coordination of development, using the Drosophila eye as an experimentally amenable system. To allow genetic, developmental and molecular approaches to the problem, in the context of otherwise normal development, experiments focus on the role of ultraspiracle (usp), the Drosophila RXR, in control of morphogenetic furrow movement and the earliest stages of cellular differentiation in the eye.The developing Drosophila eye offers an excellent model to study an RXR-mediated activation/repression system. The eye primordium is marked by a visible constriction, the morphogenetic furrow, separating the posterior and anterior regions. The morphogenetic furrow moves from posterior to anterior across the primordium. Cells in the anterior region are undifferentiated and have not committed to any particular fate. In the posterior cell commitment and differentiation occur in a reproducible and stereotypical manner.Normal movement of the morphogenetic furrow and normal differentiation posterior to the furrow require the function of ultraspiracle. In the absence of ultraspiracle, the furrow moves more quickly than normal and cell commitment in the posterior occurs more rapidly. These phenotypes suggest repression by ultraspiracle-containing dimers and the possibility of both relief of repression and activation near or within the morphogenetic furrow. A candidate co-repressor is expressed in the eye.Work will be directed at the role of usp, its dimerization partners and co-repressor partners in the control of furrow movement and post-furrow differentiation. Experiments will test the independence of pre-furrow and post-furrow functions of usp as well as specifically addressing the mechanism of anterior repression and the possibility and mechanism of ligand-induced activation within the morphogenetic furrow. The most likely nuclear receptor partner for repression and activation by usp will be tested for function in this system using in vitro produced dominant mutations.The high degree of similarity between the regulatory systems operating in the Drosophila eye development and in mammalian limb, heart, eye and nervous system makes it extremely likely that the results of these studies will give insight into multiple processes in other organisms.