Analysis of the role of Rho GTPases in epithelial cells
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Rho GTPases are a family of small GTP binding proteins that function as molecular switches for the control of a variety of fundamental cellular processes, and therefore represent potentially vital proteins for skin homeostasis. Through ultrastructural analysis of murine skin bearing specific gene deletions in keratinocytes, the involvement of Neural Wiskott-Aldrich syndrome protein (N-WASP) in maintaining cell-cell and cell-matrix adhesion, of RhoA in maintaining epidermal integrity including the dermal epidermal junction (DEJ), and of Rac1 in maintaining the structure of the permeability barrier, was examined as part of wider projects and discussed in the appropriate cell biological context. It was found that these proteins are dispensable for maintaining the above aspects of the integrity of the interfollicular epidermis (IFE). The effects of Rac1 deletion in keratinocytes were also studied in relation to the maintenance of the DEJ, to the tissue localisation and arrangements of collagen fibrils and of decorin, and to the distribution and the level of protein expression of Nox1. These aspects were also investigated in the presence of irritant contact dermatitis. Primarily, these studies were conducted in 11-month-old mice, however, the DEJ was also studied in younger mice. These studies mainly showed: sporadic duplication of the basement membrane and increased thickness of the Lamina lucida due to the lack of Rac1, which were more marked in older mice; alteration in the size distribution of the diameter of collagen fibrils in relation to a higher inflammatory status; and clear expression of Nox1 in IFE under normal conditions, which was not affected by deletion of Rac1 or inflammation. Other than adding important ultrastructural knowledge to the cell biology of the N-WASP, Rac1 and RhoA, this thesis revealed unknown functions of Rac1 in the homeostasis of the DEJ and dermal collagen, and contributed to clarify the role of Rac1 in the regulation of Nox1 function in keratinocytes in vivo.
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