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dc.contributor.advisor Lechler, Terry en_US
dc.contributor.author Sumigray, Kaelyn D. en_US
dc.date.accessioned 2012-01-10T15:59:07Z
dc.date.available 2013-12-30T05:30:08Z
dc.date.issued 2011 en_US
dc.identifier.uri http://hdl.handle.net/10161/5009
dc.description Dissertation en_US
dc.description.abstract <p>Microtubules often adopt non-centrosomal arrays in differentiated tissues, where they are important for providing structure to the cell and maintaining polarity. Although the formation and organization of centrosomal arrays has been well-characterized, little is known about how microtubules form non-centrosomal arrays.</p><p>In the mouse epidermis, centrosomes in differentiated cells lose their microtubule-anchoring ability through the loss of proteins from the centrosome. Instead, microtubules are organized around the cell cortex. The cell-cell adhesion protein desmoplakin is required for this organization. Our model is that desmoplakin recruits microtubule-anchoring proteins like ninein to the desmosome, where they subsequently recruit and organize microtubules.</p><p>To test this model, we confirmed that the microtubule-binding proteins Lis1, Ndel1, and CLIP170 are recruited by desmoplakin to the cell cortex. Furthermore, by creating an epidermis-specific conditional Lis1 knockout mouse, I found that Lis1 is required for cortical microtubule organization. Surprisingly, however, Lis1 is also required for desmosome stability. This work reveals essential desmosome-associated components that control cortical microtubule organization and unexpected roles for centrosomal proteins in epidermal function.</p><p>Although Lis1 is required for microtubule organization, it is not sufficient. I created a culture-based system to determine what other factors may be required for cortical organization for microtubules. My work reveals that stabilization of the microtubules is sufficient to induce their cortical organization. Functionally, cortical microtubules are important for increasing the mechanical integrity of cell sheets by engaging adherens junctions. In turn, tight junction activity is increased. Therefore, I propose that cortical microtubules in the epidermis are important in forming a robust barrier by cooperatively strengthening each cell-cell junction.</p><p>To determine whether desmosomes play similar roles in simple epithelia as stratified epithelia, I examined intestinal epithelial-specific conditional desmoplakin conditional knockout mice. Unexpectedly, I found that desmoplakin is not required for cell-cell adhesion and tissue integrity in the small intestine. Furthermore, it does not organize intermediate filaments. Desmoplakin is required, however, for proper microvillus architecture. </p><p>Overall, my studies highlight novel tissue-specific roles for desmosomes, in particular desmoplakin, in organizing and integrating different cytoskeletal networks. How desmoplakin's function is regulated in each tissue will be a new interesting area of research.</p> en_US
dc.subject Cellular biology en_US
dc.subject Developmental biology en_US
dc.subject adhesion en_US
dc.subject barrier en_US
dc.subject centrosome en_US
dc.subject cytoskeleton en_US
dc.subject desmosome en_US
dc.subject microtubules en_US
dc.title Novel Roles for Desmosomes in Cytoskeletal Organization en_US
dc.type Dissertation en_US
dc.department Cell Biology en_US
duke.embargo.months 24 en_US

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