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

Subject Area Hematology, Oncology
Cardiology, Angiology
Term from 2014 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 261607756
 
Final Report Year 2025

Final Report Abstract

Platelets are small, anuclear cells that are produced predominantly in the bone marrow by polyploid precursor cells called megakaryocytes (MK). Platelets are major regulators of thrombotic and thrombo-inflammatory diseases and crucial to maintain vascular integrity. Platelet biogenesis and function essentially involve profound cytoskeletal rearrangements. While detailed insights have been gained into the function of tubulin in these processes, the role of the actin cytoskeleton is largely elusive. In this project, we analyzed the complex functions of actin-binding proteins in thrombopoiesis and platelet function in mice. By using knock-out mouse lines we could show that deficiency of Profilin 1 (Pfn1) in MK and platelets results in microthrombocytopenia and a Wiskott-Aldrich-Syndrome (WAS)-like phenotype and an associated enhanced inactivation of platelet integrins. In contrast, Twinfilin 2a (Twf2a)-deficient mice exhibited a moderate macrothrombocytopenia which was associated with sustained integrin activity and, consistently, increased reactivity of the affected platelets. Further studies investigated redundant functions of Twf, Cofilin and Pfn in thrombopoiesis and platelet function. Furthermore, we gained fundamental insights into the functions of Coactosin-like protein 1 (Cotl1), Thymosin β4 (Tmsb4x) und cyclase associated proteins (Cap1, Cap2) in these processes. We could show that Cotl1 in platelets serves as an integrator of biomechanical and leukotriene signaling in hemostasis and thrombosis. Loss of Tmsb4x resulted in a mild platelet production defect and a pronounced impairment of thrombus formation under high shear flow which could be reverted by exogenous Tmsb4x showing distinct functions of cellular and released Tmsb4x in MK/platelet biology. Analysis of Cap1-KO mice revealed marked defects in actin-/microtubule-dynamics which translated into defective proplatelet formation from MK and severely impaired thrombus formation under flow in vitro and in vivo. In contrast, Cap2-deficiency caused an unexpected platelet hyperreactivity; the underlying molecular mechanism is still under investigation. Taken together, our studies have provided significant new insights into the function of prominent actin-binding proteins in MK and platelets, which contributed to a better understanding of cytoskeletal dynamics in platelet biogenesis and function. Parts of the results may contribute to a better diagnosis and/or, possibly, treatment of platelet function defects.

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