Research profile and aims
Welcome to the Magin lab homepage! Our group has a major interest in molecular mechanisms governing epithelial differentiation, regeneration and pathogenesis, using the function of the epithelial keratin cytoskeleton as a paradigm.
Protein families are a hallmark of higher eukaryotes. Therefore, understanding the complexity of the keratin family serves as a paradigm. Among the questions we are studying, are the following:
- What is the functional significance of keratin diversity?
- Are there unique or shared functions? What is their function during skin development?
- What is the role of keratins in cell adhesion?
- How do they control skin barrier formation and maintenance?
- How do keratin mutations cause disease?
- What is the role of keratins and keratinocytes in chronic inflammatory disorders like atopic dermatitis and psoriasis?
- What is their role in tumour formation and metastasis?
- How can we develop rational therapy concepts for keratinopathies?
Keratins form the major cytoskeleton of all epithelia and comprise >50 genes, subdivided into the type I and type II gene families, each numbering ~25 members in the human and the mouse. These genes are organized in two separate contiguous clusters spanning 0.68 and 1Mb of the mouse and human genomes, without known intermittent genes. Type I and type II keratins are differentially regulated in a pairwise fashion in various epithelia making up the body. All keratins share a similar domain structure, with an alpha-helical rod domain that is flanked by non-helical head and tail domains. They assemble into heterodimeric subunits through coiled-coils which subsequently form long filaments. In epithelial cells, keratin filaments are connected to specialized epithelial junctions, namely desmosomes and hemidesmosomes to form a supracellular cytoskeleton that contributes to the stability of the epidermis and other epithelia. While embryonic and simple epithelia express 2-6 keratins, many stratified epithelia display >10 different keratins per cell. Upon environmental stress, altered proliferation, wound healing and during malignant transformation, keratin expression is altered, possibly to endow cells with altered adhesive, migratory and proliferative capacity. How keratin diversity contributes to such changes at the molecular level is not well understood.
Epithelial tissues cover external and internal body surfaces and protect against infections, chemical and physical stress and dehydration. Furthermore, epithelia play a vital role in cell communication and regulation of metabolism. Our favourite epithelial tissue is the epidermis which is one of the tissues with an enormous regenerative potential. Because genetic and other alterations become immediately visible, the epidermis is ideally suited to study molecular mechanisms underlying phenotypic changes. Moreover, the skin and its major cell type, the keratinocyte, are easily accessible.
We follow the hypothesis that members of the keratin multigene family play a major role in the spatiotemporal regulation of the above epithelial functions, by acting as cell type-specific architectural and regulatory proteins, disruption of which causes barrier and chronic inflammatory disorders. This hypothesis is strongly supported by the large number of cell-specific epithelial disorders caused by mutations in 20 of the 54 keratin genes and by mouse models (http://www.interfil.org/). Mutations in epidermal keratin genes, for example, cause a wide range of skin disorders (e. g. Epidermolysis bullosa simplex), some of which can be life-threatening. Moreover, we hypothesize that reorganization of the keratin cytoskeleton is a major event in carcinogenesis and metastasis.
The aim of our research is to elucidate molecular mechanisms by which keratin isotypes contribute to epidermal morphogenesis, cell adhesion, barrier function, regeneration and disease. Understanding these mechanisms is necessary to resolve pathomechanisms underlying keratin-associated disorders as a major prerequisite for the development of molecular therapies, an aspect which we address in several projects.
To achieve these aims, we work with 3 model systems, namely genetically altered mice, Drosophila and cultured keratinocytes, in combination with a wide range of cell biological, biochemical and molecular genetics approaches. In addition to mice carrying deletion of individual keratin genes, we have recently succeeded to establish mouse lines in which all 28 type I and 26 type II keratin genes can be deleted conditionally, using cre-lox mediated genome engineering. These mouse lines form the basis for a strategy we called “delete and replace” to elucidate keratin function. Using these mice and keratinocytes derived therefrom, we have now identified previously unknown roles of keratins in desmosome-based adhesion and in the control of keratinocyte-based inflammatory skin disorders. These discoveries were featured in special commentaries in the Journal of Cell Biology (2013) and the Journal of Cell Science (2012). Moreover, in collaboration with biophysicists, we showed that keratins are major determinants of cell stiffness and invasiveness. This finding has great relevance for tumor biology and tissue engineering.
Despite two decades of research, pathomechanisms of human keratin disorders are not well understood, hindering the development of molecular therapies. To address these mechanisms, we have initiated an unbiased genetic screen, using Drosophila as a model organism for the expression of keratin disease mutants. Based on results, we will perform genetic rescue experiments to identify the underlying genes. In the next step, we will ask whether these genes are conserved in mice and humans and test them in appropriate cell culture and animal models. We expect that this strategy pave the way for novel, molecular therapies of keratin disorders and moreover provides novel insights into pathways regulating the keratin cytoskeleton.
Our group belongs to the Natural Science Faculty (Fakultät für Biowissenschaften, Pharmazie und Psychologie) at the University of Leipzig and the Translational Centre for Regenerative Medicine (TRM). While we have a major focus at basic research, membership at the TRM allows us to extend our findings into translational research. At the TRM, we analyze disease mechanisms of skin keratin disorders (eg. epidermolysis bullosa simplex, EBS), including the role of keratins in stem cell maintenance and evaluate therapy approaches for EBS based on small molecules. These investigations aim to improve our understanding of keratinocytes for therapeutic applications.