Cadherin function in epidermal morphogenesis and barrier formation

• Antragstellerin: Professorin Dr. Carien Niessen, Ph.D.
• Fachliche Zuordnung: Dermatologie
• Förderung: Förderung von 2007 bis 2010
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 48677787

Cadherin adhesion molecules are key determinants of morphogenesis and tissue architecture. Besides supporting cell-cell adhesion, cadherins can affect a wide range of cellular functions that include activation of cell signaling pathways, regulation of the cytoskeleton, and control of cell polarity. To determine the role of E-cadherin in stratified epithelium of the epidermis, we have conditionally inactivated its gene in mice. Loss of E-cadherin in the epidermis results in perinatal death of mice due to extensive transepidermal water loss. Surprisingly, no difference was found in the barrier function of the cornified layer. Tight junctions, however, were both structurally and functionally impaired, thus explaining the water loss. Intercellular cohesion was not obviously altered but lack of E-cadherin did alter the localization of signaling molecules such as atypical PKC and Rac, suggesting that signaling but not adhesion is responsible for E-cadherin mediated tight junction formation. An important question for the next period is how E-cadherin regulates tight junction formation in the epidermis and if this requires its adhesive or signaling function. For this different E-cadherin constructs will be used that can rescue either adhesion or signaling and examine if they can restore in vitro barrier formation in E-cadherin negative keratinocytes. Other important questions are how E-cadherin, which is expressed in all layers of the epidermis, restricts tight junction formation to the granular layer and which molecules are downstream of Ecadherin to regulate tight junctions. Obvious candidates are aPKC and the small GTPase Rac. Lastly, E-cadherin has been implicated in many other functions such as regulation of differentiation and proliferation and this function may have been compensated by the observed upregula3 tion of P-cadherin, the other classical cadherin present in epidermis. We therefore would like to inactivate both P-cadherin and E-cadherin in the epidermis to examine the role of classical cadherins in epidermal morphogenesis, homeostasis and disease.

• DFG-Verfahren: Sachbeihilfen