Stress and Transglutamination lead to Cornification

The cornified skin was an important step in the evolution of land-dwelling vertebrates and allowed them to conquer the land and live independent of water. Their skin protects them against environmental hazards such as UV-radiation, pathogens, and desiccation. The skin of land-dwelling vertebrates is built by the family of transglutaminases (TGM), particularly the enzyme TGM1. TGM1 crosslinks structural proteins to build a stable and cornified cell layer. Mutations of TGM1 can lead to severe skin diseases in humans. The most important substrates of TGM1 in the skin belong to the epidermal differentiation cluster (EDC) which evolved from S100 proteins in the last common ancestor of terrestrial vertebrates. S100 proteins protect the organisms against infections and other forms of cellular stress. TGM1 and related proteins were identified in all vertebrates and the lancelets (cephalochordata), whereas S100 proteins were identified in all vertebrates. Lancelets and primary aquatic vertebrates such as lamprey, sharks, and bony fish do not develop a cornified layer on their regular skin. Hence, TGM1, which is crucial for the normal development of the skin of land- dwelling vertebrates, is much older than terrestrial vertebrates. The function TGM1 in in lancelets and primary aquatic vertebrates is not known. At first, this project aims to study TGM1 in lancelets. The gene editing tool CRISPR will be used to deactivate TGM1 enzymes in the lancelets to study their functions. Additionally, TGM1 and their S100 substrates of primary aquatic vertebrates will be studied in their skin. This project further aims to test the hypothesis that transglutamination and drought stress were potential evolutionary drivers for the cornified skin of terrestrial vertebrates. For this, the impact of drought stress on the skin of zebrafish will be tested to better understand the molecular mechanisms behind the evolution of the cornified skin. All in all, this project will cover important aspects of vertebrate skin biology and contribute to an improved understanding of the evolution of the cornified skin.