REGULATION OF THE MAMMALIAN GDF6 GENE

骨形态发生中的生长分化因子亚家族 蛋白(BMP)蛋白参与启动关节的形成 四肢。Gdf5和Gdf6都在连接前的区域表达 肢体发育，在条纹中，细胞死亡和 分化会在骨骼元素之间产生关节。证据来自 靶向突变表明GDF蛋白起信号作用 分子做到这一点；然而，Gdf5/6表达的机制 具体发生在区域间的情况不详。我建议找出 控制Gdf6表达的调控元件，并使用这些 确定控制区间表达的上游因素的要素。 这将通过驱动LacZ报告基因的表达来实现 在体内使用来自小鼠Gdf6基因位点的大基因组克隆。 对正确的GDF6结构的临界区分析 表达将导致特定控制序列的识别 以及与它们相互作用的因素。此外，我还将使用这些 在发育中的关节中驱动其他基因表达的元素。这 将使测试关节中其他基因的功能成为可能 功能，包括BMP家族的其他成员，如GDF5。这个 拟议的研究将为了解这种机制提供重要的见解。 信号蛋白在发育过程中和应该通过什么来调节 深入了解软骨和滑膜关节的正常过程 队形。

The growth differentiation factor (GDF) subfamily of bone morphogenetic protein (BMP) proteins is implicated in initiating joint formation in limbs. Both Gdf5 and Gdf6 are expressed in pre-joint interzones during limb developments, in stripes where changes in cell death and differentiation produce joints between skeletal elements. Evidence from targeted mutations indicate that Gdf proteins function as signaling molecules to do this; however, the mechanisms by which Gdf5/6 expression occurs specifically in the interzone are unknown. I propose to identify the regulatory elements that control Gdf6 expression, and to use these elements to identify upstream factors controlling interzone expression. This will be accomplished by driving expression of a lacZ reporter genes in vivo using large genomic clones derived from the mouse Gdf6 gene locus. Analysis of the critical regions of this construct for correct Gdf6 expression will lead to the identification of specific control sequences and the factors that interact with them. In addition, I will use these elements to drive expression of other genes in developing joints. This will make it possible to test the function of other genes in joint function, including other members of the BMP family such as Gdf5. The proposed studies will provide important insight into the mechanisms through which signaling proteins are regulated during develop and should provide insight into the normal process of cartilage and synovial joint formation.