Desmosomes are essential cell-cell adhesion structures that provide mechanical integrity to tissues. Disruption of desmosomes leads to a range of diseases in man including skin fragility and blistering disorders as well as cardiomyopathies. The textbook view of desmosomes is that they are rather passive structures that simply bind to the intermediate filament cytoskeleton. We are now beginning to appreciate that desmosomes are both more dynamic and have more functions than previously thought. For example, we have shown that desmosomes control microtubule organization in the epidermis and cultured keratinocytes. In this application, we focus on how desmosomes control the organization of cytoskeletal networks. Our central hypothesis is that the desmosome actively organizes both intermediate filaments and microtubules through recruitment of a protein complex that is usually found at the centrosome. Some of the novel desmosomal proteins in this complex, including Lis1 and NDEL1, are known to control microtubule and intermediate filament organization in other tissues. By understanding both how these proteins are recruited to desmosomes and their functional role there, we will greatly expand our knowledge of how desmosomes control the cytoskeleton. This will allow us to specifically disrupt microtubule organization in differentiated epidermis, and to determine the physiological function of cortical microtubules in these cells. To accomplish this, we will generate and characterize mouse models in which centrosomal proteins are not recruited to desmosomes. This will directly test the physiological role of this novel desmosomal function. Second, we will determine how loss of Lis1 in the epidermis leads to defects in epidermal integrity, desmosome architecture, and microtubule organization. Third, we will determine the role of the novel keratin-binding protein, NDEL1, in controlling keratin filament organization downstream of the desmosome. This work will lead to a mechanistic understanding of how desmosomes reorganize the underlying cytoskeleton and to a greater understanding of why desmosome disruption results in such a diversity of pathological phenotypes.

Public Health Relevance

Desmosomes are cell-cell adhesion structures that provide mechanical integrity to cells by linking to the underlying cytoskeleton network. Disruption of desmosomes causes epidermal fragility, skin blistering, and cardiomyopathies. We will characterize novel mechanisms that desmosomes use to reorganize the cytoskeleton. This will allow an understanding of how desmosome disruption results in such a diversity of pathological phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR055926-04
Application #
8303015
Study Section
Cell Structure and Function (CSF)
Program Officer
Baker, Carl
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$333,590
Indirect Cost
$119,750
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Huebner, Robert J; Lechler, Terry; Ewald, Andrew J (2014) Developmental stratification of the mammary epithelium occurs through symmetry-breaking vertical divisions of apically positioned luminal cells. Development 141:1085-94
Sumigray, Kaelyn; Zhou, Kang; Lechler, Terry (2014) Cell-cell adhesions and cell contractility are upregulated upon desmosome disruption. PLoS One 9:e101824
Ray, Samriddha; Foote, Henry P; Lechler, Terry (2013) beta-Catenin protects the epidermis from mechanical stresses. J Cell Biol 202:45-52
Foote, Henry P; Sumigray, Kaelyn D; Lechler, Terry (2013) FRAP analysis reveals stabilization of adhesion structures in the epidermis compared to cultured keratinocytes. PLoS One 8:e71491
Seldin, Lindsey; Poulson, Nicholas D; Foote, Henry P et al. (2013) NuMA localization, stability, and function in spindle orientation involve 4.1 and Cdk1 interactions. Mol Biol Cell 24:3651-62
Zhou, Kang; Muroyama, Andrew; Underwood, Julie et al. (2013) Actin-related protein2/3 complex regulates tight junctions and terminal differentiation to promote epidermal barrier formation. Proc Natl Acad Sci U S A 110:E3820-9
Sumigray, Kaelyn D; Lechler, Terry (2012) Desmoplakin controls microvilli length but not cell adhesion or keratin organization in the intestinal epithelium. Mol Biol Cell 23:792-9
Sumigray, Kaelyn D; Chen, Hsin; Lechler, Terry (2011) Lis1 is essential for cortical microtubule organization and desmosome stability in the epidermis. J Cell Biol 194:631-42