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.
Showing the most recent 10 out of 29 publications
