CELLULAR AND DEVELOPMENTAL FUNCTIONS OF MENA

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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.