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
