Nuclear hormone receptors and epidermal differentiation

The skin is the human organ with the largest surface area, and it provides the body’s first line of defense against dehydration, injury, infection, and physical and environmental challenges. Among the numerous cells present in the skin epidermis, keratinocytes are the predominant cell type and are also the major contributor to the protective functions of this organ. Keratinocytes undergo an elaborate terminal differentiation process to form a constantly renewing mechanical and chemical barrier between the body and its immediate environment. Therefore, keratinocyte differentiation is an essential process in the production of the epidermal barrier. Four cell layers can be distinguished morphologically in the healthy epidermis: the stratum basale, stratum spinosum, stratum granulosum, and stratum corneum. The stratum basale is the proliferative cell compartment, and it keeps the epidermis firmly anchored to the basal lamina. The differentiation and keratinization processes begin in the stratum spinosum through the production of fibrillar proteins that aggregate into tonofibrils and are involved in desmosome formation, which generate strong connections between adjacent keratinocytes. Cells of the stratum granulosum are characterized by keratohyalin granules, which contain proteins that promote the hydration and cross-linking of keratin. Cells close to the stratum corneum secrete lamellar bodies into the extracellular space; lamellar bodies are composed of proteins and lipids and participate in the formation of the hydrophobic lipid envelope, which is important for barrier properties. These cells lose their organelles and become dead corneocytes of the stratum corneum. The formation of the epidermal barrier relies on controlled transcriptional changes that lead the cells through a gradual terminal differentiation process. In this chapter, we discuss the existing knowledge concerning the differentiation-dependent regulation of gene expression in keratinocytes by nuclear hormone receptors.