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The role of BCR signalling and the gap junction protein Cx43 in B lymphocyte cytoskeletal rearrangements Machtaler, Steven Brian Alfred

Abstract

Regulation of the cytoskeleton is an essential process for normal B lymphocyte development and immune system regulation. Though this biological process is important to normal function, its regulation is not completely understood. An important receptor required to initiate antigen-mediated cytoskeletal rearrangements in B lympocytes is the B cell antigen receptor (BCR). This is a multimeric protein complex that contains two signalling proteins, Igα and Igβ, which become phosphorylated after antigen engagement leading to signalling cascades which result in cytoskeletal rearrangements and differentiation. The gap junction protein connexin43 (Cx43) is widely expressed in mammalian cells, forming intercellular channels for the transfer of small molecules between adjacent cells as well as hemichannels that mediate bidirectional transport of molecules between the cell and the surrounding environment. Cx43 has recently been shown to regulate cell adhesion and migration in neurons and glioma cells, biological processes dependent on the rearrangement of the cytoskeleton, however its role in B lymphocytes remains unknown. The aim of this thesis was to determine the importance of the B cell antigen receptor (BCR) member Igα and the gap junction protein connexin43 (Cx43) to the regulation of the B cell cytoskeleton. I show here that the cytoplasmic domain of Igα was necessary for maximal BCR-mediated cytoskeletal rearrangements, and that the cytoplasmic domain of Igβ was not sufficent to conferthis phenotype. In order to determine if Cx43 was required for B cell cytoskeletal rearrangements, both loss-of and gain-of-function approaches were used. I show that Cx43 was necessary for sustained BCR, integrin and chemokine-mediated Rap1 activation, as well as B cell spreading, adhesion, motility and migration. I also identified that the C-terminal domain of Cx43 was necessary for these processes, suggesting that this may be a site where proteins which regulate the cytoskeleton are recruited to. This thesis provides the first evidence that Cx43 is essential for regulation of the B cell cytoskeleton.

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