Function of actin-monomer-binding proteins in megakaryocytes and platelets

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The regulated reorganization of the actin and tubulin cytoskeleton is of paramount importance for platelet biogenesis by their precursor cells, the megakaryocytes (MKs). In addition, essential platelet functions, such as shape change, granule release, adhesion/ spreading on immobilized extracellular matrix (ECM) components and aggregation, strictly depend on fine-tuned cytoskeletal rearrangements. The functions of the small actin-monomer-binding proteins twinfilin1 (Twf1), twinfilin2a (Twf2a), cyclase-associated protein 1 (CAP1), cyclase-associated protein 2 (CAP2), thymosin beta4 (Tmsb4x), cofilin (Cof) and profilin1 (Pfn1) in the regulation of cytoskeletal dynamics in nucleated cells are partially defined in vitro but their function in vivo remains largely unknown, particularly in platelets. In our preliminary work, we identified critical roles for ADF/Cof and Pfn1 in platelet production and function. Further data also point to an important role of Twf2a in these processes and provide the first evidence in vivo for an interaction of Twf1 and Cof in megakaryocytes and platelets. In the proposed project, we aim to dissect the physiological roles of Twf and their hypothetical interaction partners in platelet biogenesis and function. To this end, we will generate mouse lines with constitutive or MK-/platelet-specific single, double or triple-deficiencies in Twf1, Twf2a, CAP1, CAP2, Tmsb4x, Cof1 and Pfn1 and subject them to detailed in vitro and in vivo studies on platelet biogenesis and function. We expect that these studies will contribute to a better understanding of cytoskeletal functions and provide novel insights into the regulation of the actin- and tubulin cytoskeleton by small actin-monomer-binding proteins. In addtion, the expected results may be of relevance for the diagnosis and treatment of disorders of the hematopoietic system.