Novel Roles for Desmosomes in Cytoskeletal Organization

dc.contributor.advisor

Lechler, Terry

dc.contributor.author

Sumigray, Kaelyn D.

dc.date.accessioned

2012-01-10T15:59:07Z

dc.date.available

2013-12-30T05:30:08Z

dc.date.issued

2011

dc.department

Cell Biology

dc.description.abstract

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.

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.

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.

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.

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.

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.

dc.identifier.uri

https://hdl.handle.net/10161/5009

dc.subject

Cellular biology

dc.subject

Developmental biology

dc.subject

adhesion

dc.subject

barrier

dc.subject

centrosome

dc.subject

cytoskeleton

dc.subject

desmosome

dc.subject

microtubules

dc.title

Novel Roles for Desmosomes in Cytoskeletal Organization

dc.type

Dissertation

duke.embargo.months

24

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
Sumigray_duke_0066D_11175.pdf
Size:
14.05 MB
Format:
Adobe Portable Document Format

Collections