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Store-operated Ca(2+) entry (SOCE) is the major route of Ca(2+) influx in platelets. The Ca(2+) sensor stromal interaction molecule 1 (STIM1) triggers SOCE by forming punctate structures with the Ca(2+) channel Orai1 and the inositol trisphosphate receptor (IP(3)R), thereby linking the endo-/sarcoplasmic reticulum to the plasma membrane. Here, we identified the BAR domain superfamily member bridging integrator 2 (BIN2) as an interaction partner of STIM1 and IP(3)R in platelets. Deletion of platelet BIN2 (Bin2(fl/fl,Pf4-Cre) mice) resulted in reduced Ca(2+) store release and Ca(2+) influx in response to all tested platelet agonists. These defects were a consequence of impaired IP(3)R function in combination with defective STIM1-mediated SOC channel activation, while Ca(2+) store content and agonist-induced IP(3) production were unaltered. This severely defective Ca(2+) signaling translated into impaired thrombus formation under flow and a protection of Bin2(fl/fl,Pf4-Cre) mice in models of arterial thrombosis and stroke. Our results establish BIN2 as a central regulator of platelet activation in thrombosis and thrombo-inflammatory disease settings.

Dystrophic epidermolysis bullosa (DEB) is a severe skin fragility disorder associated with trauma-induced blistering, progressive soft tissue scarring, and increased risk of skin cancer. DEB is caused by mutations in type VII collagen. In this study, we describe the generation of a collagen VII hypomorphic mouse that serves as an immunocompetent animal model for DEB. These mice expressed collagen VII at about 10% of normal levels, and their phenotype closely resembled characteristics of severe human DEB, including mucocutaneous blistering, nail dystrophy, and mitten deformities of the extremities. The oral blistering experienced by these mice resulted in growth retardation, and repeated blistering led to excessive induction of tissue repair, causing TGF-beta1-mediated contractile fibrosis generated by myofibroblasts and pseudosyndactyly in the extremities. Intradermal injection of WT fibroblasts resulted in neodeposition of collagen VII and functional restoration of the dermal-epidermal junction. Treated areas were also resistant to induced frictional stress. In contrast, untreated areas of the same mouse showed dermal-epidermal separation following induced stress. These data demonstrate that fibroblast-based treatment can be used to treat DEB in a mouse model and suggest that this approach may be effective in the development of clinical therapeutic regimens for patients with DEB.