Epithelia form physical barriers that separate and protect the internal milieu of the body from its external environment and pathogens. The formation of epithelia requires the coordination of multiple cellular processes that include the assembly of a series of specialized cell-cell junctions responsible for cell to cell adhesion, the establishment of an impermeable barrier, and provide a scaffold for signals to generate epithelial polarity that establish the differential distribution of cell proteins, lipids, and functions to apical and basolateral surfaces. Adhesive junction turnover are required for the movement of epithelia as occurs during normal development and in pathologic conditions such as cancer metastasis. This process has been morphologically and genetically described as an epithelial to mesenchymal transition (EMT). EMT has emerged as a central biologic process not only during embryonic development but also in states of chronic inflammation and fibrosis, wound healing, and cancer metastasis in the adult organism. While many different environmental signals induce EMT they all converge to activate nuclear transcription factors that effect an EMT gene program through repression of epithelial genes, particularly cell-cell adhesive receptors, and up-regulation of mesenchymal genes. A fundamental question then is to determine whether and how cell surface adhesive events and nuclear processes communicate with one another to coordinate dynamic epithelia biogenesis and morphogenesis. Our laboratory has identified the Ajuba LIM protein family as novel components of Adherens Junctions (AJ) and that are actively recruited to newly forming E-cadherin-dependent junctions. As such they contribute to the formation, stability, and function of junctional complexes. These proteins also translocate to the nucleus, where their function has proved to be more elusive. We have now identified the Ajuba LIM proteins as interacting with the Snail family of transcriptional repressors and act as nuclear co-repressors. Snail family proteins are central regulators of EMT during development and cancer progression. Like Snail, Ajuba LIM proteins were found to be important for the development of neural crest derivatives, in vivo. Thus, Ajuba LIM proteins, analogous to 2-catenin during Wnt signaling, have the potential to coordinate cell surface adhesive events with nuclear responses during epithelia biogenesis/morphogenesis. The general aims of this proposal then are to first determine how the Ajuba LIM protein family influences epithelial cell junction formation, stability, and function and to determine the biologic and functional implications of the nuclear Ajuba LIM protein. Epithelium cover all body surfaces (outside and inside) and protect us from environmental toxins and pathogens. Therefore understanding how epithelium develop, and how they are maintained is critical to human health and welfare. Moreover how epithelium develops is very similar to how epithelial cancers (e.g., breast, colon, lung) spread, or metastasis, in adults. We have identified a family of proteins that contribute to the formation of epithelium. The goal of this proposal is to understand how this family of protein does so. This knowledge should increase our capacity to treat disorders of the epithelium such as skin disorders, cancer spread, and tissue scaring in response to injury.
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