Steed, E.; (2012) Functional analysis of MarvelD3, a novel transmembrane protein of the tight junction. Doctoral thesis , UCL (University College London).

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Abstract

Tight junctions are an intercellular adhesion complex of epithelial and endothelial cells. They form a paracellular diffusion barrier and interact with a network of intracellular signalling mechanisms that control junction function, gene expression and cell behaviour. Tight junctions are formed by multiprotein complexes containing cytosolic and transmembrane proteins. In this thesis I have identified a novel fourpass transmembrane protein of the tight junction called MarvelD3 and begun to analyse its function in the regulation of intracellular signalling pathways from the junction. There are two isoforms of MarvelD3, both of which show a broad tissue distribution and are expressed in different types of epithelial and endothelial cells. MarvelD3 co-localises with occludin at the tight junction in epithelial cells. I have found that MarvelD3 is not necessary for junction formation, but may have a role in the regulation of ion conductance properties of the tight junction. Functional analyses combining loss- and gain-of-function approaches in epithelial cell lines have further identified a role for MarvelD3 in the regulation of cell proliferation, migration and the cellular response to hyperosmotic shock. MarvelD3 expression regulates levels of active c-Jun N-terminal kinase (JNK) and AP1 signalling, possibly via an interaction between its N-terminus and the MAP kinase kinase kinase MEKK1. I have also shown MarvelD3 to be implicated in regulation of the actin cytoskeleton, affecting leading edge formation in migrating cells and cytoskeletal rearrangements in response to hyperosmotic shock. I will also describe some initial studies conducted in Xenopus laevis embryos in which depletion of Xenopus MarvelD3 by morpholino injection results in curvature of the anterioposterior axis and reduced pigmentation, possibly resulting from a defect in neural crest cell migration.

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