DSSS - The zebrafish skin: development, carcinogenesis and regeneration

The skin of zebrafish, although lacking cornification of upper layers of the adult epidermis, is highly similar to the human skin, including highly conserved genetic control systems – which makes it to a good in vivo model for various human skin diseases.

In the first part of my seminar, I describe two zebrafish mutants with embryonic epidermal hyperplasia, one caused by loss-of-function mutations in the Hepatocyte Growth Factor Activator Inhibitor (hai1a), and the other by loss-of-function mutations in a beta subunit of a Na+/K+ pump / ATPase (atp1b1a). Surprisingly, both mutations affect the epidermis via an aberrant hyperactivation of Matriptase 1a (st14a), a type 2 transmembrane S/T kinase with described oncogenic effects in multiple types of carcinogenesis in human. However, due to the different modes of ST14 hyperactivation, different signal transduction pathways downstream of ST14 are activated in the two zebrafish mutants. In both cases, these intracellular pathways split up into an oncogenic and a tumor-suppressive branch, the latter of which leads to apical extrusions of living cells at the skin surface, together constituting the “double face” of ST14. In weak hai1 mutants, the tumor-suppressive branch eventually “wins”, leading to spontaneous healing of the mutant, whereas atp1b1a mutants become progressively worse, including the invasion of transformed keratinocytes into the interior of the embryos, where they form secondary tumors (metastasis). To identify potential mediators of ST14 contributing to benignity versus malignancy, we have performed comparative bulk and single cell RNA-sequencing. Functional studies of first differentially expressed factors will be presented.

The second part of my seminar deals with the adult zebrafish skin, with focus on its regenerative capacity upon wounding. In mouse and human, skin wounds develop fibrosis, leading to permanent scarring. Fish wounds also develop fibrosis in dermal compartments of the skin, which, however, fully resolves again during later stages of wound healing, leaving no scar behind. To identify the crucial players contributing to this perfect wound healing and the resolution of the fibrotic tissue, we again have performed single cell RNA-sequencing of wound biopsies at different stages of wound healing, and have started to compare the zebrafish with corresponding transcriptome data from mouse and human skin wounds. We had expected to find anti-fibrotic factors present in fish but absent in mammals, and pro-fibrotic factors present in mammals but absent in fish. However, all thus far investigated factors were present or even up- or down-regulated in comparable manners in both fish and mammalian wounds. Even transgene-driven further up-regulation of a first tested pro-fibrotic factor involved in stable cross-linking of collagen fibers in mammalian wounds (Lysylhydroxylase 2) did not compromise fibrosis resolution in zebrafish skin wounds. Together, this suggest that rather minor changes in the timing or spacing of pro- and anti-fibrotic factors make the difference between perfect versus fibrotic healing – which is good news for humans, as it might mean that rather minor therapeutic interventions could be sufficient to alleviate fibrosis and scarring.