Abstract
SummaryMany biological processes involve gene-expression regulation by alternative splicing. Here, we identify the splicing factor SRSF6 as a regulator of wound healing and tissue homeostasis in skin. We show that SRSF6 is a proto-oncogene that is frequently overexpressed in human skin cancer. Overexpressing it in transgenic mice induces hyperplasia of sensitized skin and promotes aberrant alternative splicing. We identify 139 target genes of SRSF6 in skin, and show that this SR protein binds to alternative exons of the extracellular-matrix protein tenascin C pre-mRNA, promoting the expression of isoforms characteristic of invasive and metastatic cancer in a cell-type-independent manner. SRSF6 overexpression additionally results in depletion of Lgr6+ stem cells, and excessive keratinocyte proliferation and response to injury. Furthermore, the effects of SRSF6 in wound healing assayed in vitro depend on the TNC isoforms. Thus, abnormal SR-protein expression can perturb tissue homeostasis.
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