Evolution of epidermal transglutamination

The transition from the aquatic life of fish to the terrestrial life of tetrapods was a major step in the evolutionary diversification of vertebrates and in the evolutionary history of humans. A key adaptation to the terrestrial environment was the establishment of an efficient barrier function of the skin which mainly resides in its outermost layer, the epidermis. The cross- linking of epidermal proteins by transglutaminases is essential for the skin barrier in humans and other mammals but the role of epidermal protein transglutamination in other vertebrates is not known at present. In this project, we will determine the function of epidermal transglutamination in phylogenetically diverse vertebrates. Epidermal transglutaminases and their protein substrates will be identified and characterized in non-conventional model species. Comparative genomics will be employed to determine the species distribution of transglutaminases and transglutaminase substrates with the aim of building a comprehensive model for the evolution of the epidermal transglutamination process. The results of this project will help to understand how the skin barrier of terrestrial vertebrates has evolved and how its formation and function are controlled in amphibians, reptiles, and mammals.

Transglutaminases are enzymes that cross-link proteins and thereby contribute to the mechanical resilience of the skin surface. The results of this project reveal that transglutaminases have played important roles in the evolution of the skin in vertebrates. The origin of the main transglutaminase of human skin, transglutaminase 1, could be traced back to the origin of vertebrates. This transglutaminase is conserved in mammals, birds and other land-dwelling vertebrates, but also in fish. Even jawless fish such as lampreys have transglutaminase 1 and use it in hard epithelial structures that function as teeth. Independently, another transglutaminase has acquired a function in the hardening of the epithelial egg tooth which allows hatching of birds from eggs. At least one transglutaminase is also active during the growth of cornified claws and feathers. Further transglutaminases, that have originated by the duplication and adaptation of genes in mammals, play important roles in the maturation of hair. In addition to shedding light into the mechanisms of diversification of transglutaminases during evolution, our results also point to an unexpected contribution of gene loss to shaping the repertoire of transglutaminases in humans and other species. Taken together, the results of this project establish a new model of the evolution of the skin and its appendages at the molecular level.