Terminal Differentiation of Keratinocytes

The epidermis of the skin is a dynamic tissue in which keratinocytes proliferate in the basal layer and undergo a tightly controlled differentiation program upon movement into the suprabasal layers.

The final differentiation step of epidermal keratinocytes is the conversion of living cells into corneocytes, i.e. rigid cell remnants devoid of all intracellular organelles including the nucleus. This special mode of programmed cell death involves the complete breakdown of nuclear DNA and thereby terminates the genetic control of the cellular metabolism. Deregulation of the balance between keratinocyte proliferation, differentiation and death leads to pathologic changes of the epidermis and aberrant retention of nuclear DNA in corneocytes (parakeratosis). Wide-spread skin diseases such as psoriasis, atopic dermatitis and certain forms of ichthyosis are characterized by epidermal defects which are accompanied by inflammatory reactions.

The most important function of keratinocyte differentiation is the establishment and maintenance of the stratum corneum, the outermost layer of the skin. The stratum corneum consists of corneocytes and extracellular lipids secreted by differentiated keratinocytes which together function as a barrier against the entry of chemicals and microbes from the environment and protect the body from dehydration. Although this tissue compartment lacks viable cells, it is metabolically active. Besides its critical roles in health and disease of the skin, the skin surface is an important route of administration of drugs, target of cosmetics and means of social communication. We are participating in the European Epidermal Barrier Research Network (E2BRN).

Our research is focused at the following aspects of skin biology for which we want to establish a solid knowledge base for novel diagnostic, therapeutic and cosmetic strategies:

1. Programmed cell death of epidermal keratinocytes

We are participating in the European Epidermal Barrier Research Network (E2BRN) and in the European Cooperation in Science and Technology (COST) Actions BM0903: Skin Barrier and Atopic Diseases (SKINBAD) and BM1002: Nanomechanics of intermediate filament networks (NANONET).

One of the main projects deals with the role of DNase1L2, a keratinocyte-specific endonuclease which we have characterized recently (Fischer et al., 2007). The current research project is funded by theAustrian Science Foundation grant FWF project P20043.

2. Enzymatic control of stratum corneum functions

The stratum corneum contains a plethora of enzyme activities which are critical for the maintenance of thickness, hydration and other properties essential for proper functioning of the stratum corneum. Our aim is to identify enzymes which mediate molecular reactions that are key for healthy skin. We focus on enzymes that hydrolyze biological macromolecules such as DNA, RNA and proteins as well as enzymes that modify amino acids.

3. Genetic control of the epidermis

Proliferation and differentiation of keratinocytes as well as their interactions with other cell types resident in the epidermis and in the adjacent dermis is tightly controlled by genes. Our aim is to identify and characterize those genes that are either expressed specifically in the epidermis or are subjected to keratinocyte differentiation-specific modes of regulation. This will improve the understanding of the molecular control of epidermis-specific physiological processes and may help to identify some processes which are presently uncharacterized. Furthermore, we investigate the molecular regulation of epidermal gene expression in various states of cell differentiation, inflammation and aging.

Since the genetic control of the human epidermis is the product of evolution, we aim to define the key evolutionary advancements in the genes critical for the functions in the epidermis. The phylogenetic history of all these genes will be reconstructed by comparative genomics and phylogenetic analyses in combination with expression studies in multiple model species.

4. Changes of the keratinocyte differentiation process during aging of the skin

Aging of human skin is associated with loss of elasticity and wrinkle formation, thinning of the epidermis, and changes of epidermal appendages, e.g. hair and sebaceous glands. Our aim is to characterize the molecular changes that underlie the most prominent signs of skin aging.