CELLULAR AND DEVELOPMENTAL FUNCTIONS OF MENA

为了响应细胞外刺激，许多类型的细胞改变它们的 形态学和运动，通过引发快速和动态的重排， 它们的肌动蛋白细胞骨架。 这些反应对于 胚胎发育和许多细胞类型的功能 动物 此外，系统中的扰动耦合环境 调节细胞形态和细胞-细胞或细胞-基质的线索 连接与癌症和许多其他疾病有关。 而 关于这种信号的传输方式， 穿过细胞膜，将这些信号传递到 重塑细胞结构所需的机械力仍然存在 大部分是神秘的。 Mammalian Enabled（Mena）蛋白是哺乳动物激活蛋白家族的成员。 被认为是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直接结合 profilin是一种小的肌动蛋白单体结合蛋白， 肌动蛋白聚合 Mena可能起着将profilin集中在 细胞内需要快速肌动蛋白聚合的结构， 运动的成纤维细胞的前缘或神经元的丝状伪足 生长锥 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的要求， Mena函数。 该提案将利用携带有针对性的干扰的小鼠， Mena locus. 为了了解Mena功能在发育中的作用， 将表征由Mena缺失导致的表型。 细胞 将从Mena突变体中获得，并分析 形态、粘附或移动。这些缺乏Mena的细胞也会 作为一个实验系统， 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.