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<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>
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