CELLULAR AND DEVELOPMENTAL FUNCTIONS OF MENA

作为对细胞外刺激的反应，许多类型的细胞改变它们的 通过引发快速和动态的重排而产生的形态和运动 它们以肌动蛋白为基础的细胞骨架。这样的反应对于 胚胎发育和体内多种细胞类型的功能 动物。此外，耦合环境的系统中的摄动 细胞形态和细胞-细胞或细胞-基质调节的线索 连接与癌症和许多其他疾病有关。而当 关于这种信号的传输方式，我们知道得很多。 在膜上，将这些信号转化为 重塑蜂窝结构所需的机械力仍然存在 很大程度上是神秘的。 哺乳动物激活蛋白(MENA)是一个家族的成员 被认为连接各种信号转导途径的分子 肌动蛋白细胞骨架的局部重塑。MENA直接绑定 对于Profilin，一种小的肌动蛋白-单体结合蛋白，可以刺激 肌动蛋白聚合。MENA可能会将Profilin集中在 细胞内需要快速肌动蛋白聚合的结构，如 运动性成纤维细胞的前缘或神经元的丝状足 生长锥体。拟议工作的总体目标是测试这一点 假设并推导出细胞和发育所需的 MENA功能。 该提案将利用老鼠携带有针对性的干扰 MENA轨迹。为了了解MENA功能在发育中的作用， 将描述由于失去Mena而导致的表型。单元格 将从Mena突变体中获得，并分析其像差 形态、粘连或运动。这些缺乏膜蛋白的细胞也会 作为一个实验系统，在其中执行结构功能 Mena蛋白的分析。

In response to extracellular stimuli, many types of cells alter their morphology and movement by eliciting rapid and dynamic rearrangement of their actin-based cytoskeleton. Such responses are critical for embryonic development and for the function of many cell types within animals. Furthermore, perturbation in systems coupling environmental cues to regulation of cellular morphology and cell-cell or cell-matrix connections are associated with cancer and many other diseases. While much is known about the ways in which such signals are transmitted across the membrane, the mechanisms which transduce these signals into the mechanical forces necessary to remodel cellular architecture remain largely mysterious. The Mammalian Enabled (Mena) protein is a member of a family of molecules that are thought to link various signal transduction pathways to localized remodeling of the actin cytoskeleton. Mena binds directly to profilin, a small actin-monomer binding protein that can stimulate actin polymerization. Mena may function to concentrate profilin in structures within cells that require rapid actin polymerization such as the leading edge of motile fibroblasts or the filopodia of neuronal growth cones. The overall goal of the proposed work is to test this hypothesis and to deduce the cellular and developmental requirements for Mena function. The proposal will make use of mice carrying a targeted disruption of the Mena locus. To understand the role of Mena function in development, phenotypes resulting from loss of Mena will be characterized. Cells will be derived from the Mena mutants and analyzed for aberrations of morphology, adhesion or movement. These Mena-deficient cells will also serve as an experimental system in which to conduct a structure-function analysis of the Mena protein.