Claudins: Critical Regulators of Epithelial Barriers and Morphogenesis

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Our goal is to understand how simple epithelial cell layers are transformed into complex 3D shapes. To do this, we are studying neural tube formation in the chick embryo. During this process, a flat sheet of epithelial cells is transformed into a closed tube with an overlying layer of surface ectoderm. Our data revealed new functions the claudin family of tight junction proteins that have an essential role in regulating the movement of ions and small molecules between cells. Specifically, we showed that (i) Cldn8 is required for cell shape changes that allow the neural ectoderm to bend to form the base of the neural tube, (ii) Cldn3 is required in the non-neural ectoderm to close the top of the neural tube and separate it from the surface ectoderm, and (iii) these claudins are required to localize proteins that regulate cell shape changes to the cytoplasmic face of tight junctions. Our findings, that claudins are upstream of molecules that regulate the actin-cytoskeleton and cell-shape changes, are novel.****** We hypothesize that claudins uniquely interact with protein complexes in a context-dependent manner to regulate cell-shape changes that are essential for epithelial morphogenesis. To test this hypothesis, we need to understand how claudin expression is regulated to ensure that the correct family members are appropriately expressed in particular tissues. We will identify the signaling pathways that turn on Cldn3 in non-neural ectoderm and Cldn8 in neural ectoderm (Aim 1). We will also characterize the network of protein interactions that are uniquely regulated by individual claudin family members and determine how these interactions are translated into epithelial morphogenesis (Aims 2 Claudins have received significant attention based on their altered expression patterns during disease states, yet relatively little is known regarding their normal biological function during embryonic development. We are combining classical embryology with state-of-the-art molecular approaches to define claudin function in morphogenesis. The data generated by my research program will advance our understanding of the dynamic regulation of claudins and their function during embryogenesis and allow us to develop paradigms that can be used to understand epithelial morphogenesis in the context of the whole embryo. Importantly, this program will provide unique training opportunities for undergraduate and graduate students and foster collaborations both locally and abroad.*****