REGULATED MRNA TRANSLATION IN DROSOPHILA BODY PATTERNING

描述（由申请人提供）：基因表达的适当控制是所有细胞形成和功能的基础。翻译水平的调节，曾经被认为是有限的范围，已经成为一个重要的特征，在广泛的环境中，从最早的发展阶段到神经系统的功能。最近的进展揭示了microRNA的广泛表达，其控制一种新的翻译控制形式，进一步扩大了其翻译受到调节的mRNA的比例。 在果蝇中，翻译控制和mRNA定位在卵母细胞和胚胎中的特定位置的身体图案决定因素的部署中协同作用。一个决定簇是由oskar基因编码的，它限制在卵母细胞的后极是必需的。用于实现该分布的控制包括两种形式的翻译抑制（一种与microRNA依赖性抑制惊人相似）、mRNA定位和两种或更多种形式的翻译激活。一种与奥斯卡mRNA结合的蛋白质布鲁诺（Bruno）介导一种形式的抑制和一种形式的激活。 我们的长期目标是了解这些机制中的每一个以及它们是如何协调的。当前的目标集中在布鲁诺，以及它如何在与oskar mRNA 3' UTR的一个区域结合时作为阻遏物发挥作用，以及在与3' UTR的另一个区域结合时作为激活物发挥作用。oskar mRNA的两个Bruno结合区域组织不同，一个区域的RNA可以抑制Bruno/蛋白质相互作用（二聚化），而另一个区域则不能。我们推测，结合位点的差异改变了绑定布鲁诺的构象，或限制布鲁诺可以绑定的方式。结合的Bruno的不同构象将促进或允许Bruno/蛋白质相互作用的不同选择（Bruno/Cup用于抑制，Bru/？表示激活），因此指定抑制或激活。我们将测试这个最适合当前数据的模型以及其他模型。我们还将测试布鲁诺依赖性激活涉及细胞质聚腺苷酸化的模型。 许多疾病是由不适当的基因表达引起的。我们的工作，对基因，如布鲁诺有近亲在人类中，将推进控制基因表达的基本机制的理解。

DESCRIPTION (provided by applicant): Proper control of gene expression underlies the formation and function of all cells. Regulation at the level of translation, once thought to be limited in its scope, has emerged as an important feature in a wide range of settings, from the earliest stages of development to the function of the nervous system. Recent advances that reveal the widespread expression of microRNAs, which control a novel form of translational control, further expand the fraction of mRNAs whose translation is regulated. In Drosophila, translational control and mRNA localization act coordinately in deployment of body patterning determinants at particular positions in the oocyte and embryo. One determinant is encoded by the oskar gene, and its restriction to the posterior pole of the oocyte is essential. The controls used to achieve that distribution include two forms of translational repression (one strikingly similar to microRNA-dependent repression), mRNA localization, and two or more forms of translational activation. A protein that binds to oskar mRNA, Bruno, mediates one form of repression as well as one form of activation. Our long term goal is to understand each of these mechanisms and how they are coordinated. The immediate goals focus on Bruno, and how it can function as a represser when bound to one region of the oskar mRNA 3' UTR, and as an activator when bound to another region of the 3' UTR. The two Bruno-binding regions of the oskar mRNA are organized differently, and the RNA of one region can inhibit a Bruno/protein interaction (dimerization) while the other cannot. We hypothesize that the differences in the binding sites alter the conformation of bound Bruno, or limit the manner in which Bruno can bind. The different conformations of bound Bruno would then promote or allow different options for Bruno/protein interactions (Bruno/Cup for repression, Bru/? for activation), and thus specify repression or activation. We will test this model, which best fits the current data, as well as other models. We will also test the model that Bruno dependent activation involves cytoplasmic polyadenylation. Many diseases result from inappropriate gene expression. Our work, on genes such as Bruno that have close relatives in humans, will advance understanding of the basic mechanisms that control gene expression.