Electronic Theses and Dissertations

Identifier

456

Date

2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Biology

Committee Chair

Thomas R. Sutter

Committee Member

Judith A. Cole

Committee Member

Andrew C Liu

Committee Member

Ramin Homayouni

Abstract

Keratinocyte terminal differentiation is the process that ultimately forms the epidermal barrier that is essential for mammals to survive in the ex utero environment. This process is tightly controlled by the expression of many well-characterized genes. Although a few of these genes are known to be regulated by the epidermal growth factor receptor (EGFR), an important regulator of multiple epidermal functions, neither the genome-wide scale of EGFR-mediated regulation nor the mechanisms by which EGFR signaling controls keratinocyte differentiation are well understood. Using microarray analysis we identified 2,676 genes that are regulated by EGF, a ligand of the EGFR. We further discovered, and separately confirmed by functional assays, that EGFR activation abrogates all essential metabolic processes of keratinocyte differentiation by (1) decreasing the expression of lipid matrix biosynthetic enzymes, (2) regulating numerous genes forming the cornified envelope, and (3) suppressing the expression of tight junction proteins. In organotypic cultures of skin, the collective effect of EGF impaired epidermal barrier integrity, evidenced by increased transepidermal water loss. As defective epidermal differentiation and disruption of the epidermal barrier are primary features of many human skin diseases, we used bioinformatics analysis to identify genes that are known to be associated with human skin diseases. In comparison to non-EGF-regulated genes, the EGF-regulated gene list was significantly enriched for disease genes. Further validation of the expression profiles of many of the 114 identified skin disease genes included the transcription factors GATA binding protein 3 (GATA3) and Kruppel-like factor 4 (KLF4), both required for establishing the barrier function of the skin in developing mice. These results provide a new systems level understanding of the actions of EGFR signaling to inhibit keratinocyte differentiation. As the overall effect of this inhibition is to impair epidermal barrier integrity, this study clarifies how dysregulation of the EGFR and its ligands may contribute to diseases of the skin.

Comments

Data is provided by the student.

Library Comment

Dissertation or thesis originally submitted to the local University of Memphis Electronic Theses & dissertation (ETD) Repository.

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