Shuchi Gupta

Publications

• Defective diacylglycerol-induced Ca(2+) entry but normal agonist-induced activation responses in TRPC6-deficient mouse platelets.

  Ramanathan G, Gupta S, Thielmann I, Pleines I, Varga-Szabo D, May F, Mannhalter C, Dietrich A, Nieswandt B, Braun A

  J Thromb Haemost. 03/2012;
• 10.56

  Impact points

  Megakaryocyte-specific RhoA deficiency causes macrothrombocytopenia and defective platelet activation in hemostasis and thrombosis.

  Irina Pleines, Ina Hagedorn, Shuchi Gupta, Frauke May, Lidija Chakarova, Jolanda van Hengel, Stefan Offermanns, Georg Krohne, Christoph Kleinschnitz, Cord Brakebusch, Bernhard Nieswandt

  Blood. 11/2011; 119(4):1054-63.

  Vascular injury initiates rapid platelet activation that is critical for hemostasis, but it also may cause thrombotic diseases, such as myocardial infarction or ischemic stroke. Reorganizations of the platelet cytoskeleton are crucial for platelet shape change and secretion and are thought to involv... [more] Vascular injury initiates rapid platelet activation that is critical for hemostasis, but it also may cause thrombotic diseases, such as myocardial infarction or ischemic stroke. Reorganizations of the platelet cytoskeleton are crucial for platelet shape change and secretion and are thought to involve activation of the small GTPase RhoA. In this study, we analyzed the in vitro and in vivo consequences of megakaryocyte- and platelet-specific RhoA gene deletion in mice. We found a pronounced macrothrombocytopenia in RhoA-deficient mice, with platelet counts of approximately half that of wild-type controls. The mutant cells displayed an altered shape but only a moderately reduced life span. Shape change of RhoA-deficient platelets in response to G(13)-coupled agonists was abolished, and it was impaired in response to G(q) stimulation. Similarly, RhoA was required for efficient secretion of α and dense granules downstream of G(13) and G(q). Furthermore, RhoA was essential for integrin-mediated clot retraction but not for actomyosin rearrangements and spreading of activated platelets on fibrinogen. In vivo, RhoA deficiency resulted in markedly prolonged tail bleeding times but also significant protection in different models of arterial thrombosis and in a model of ischemic stroke. Together, these results establish RhoA as an important regulator of platelet function in thrombosis and hemostasis.
• 10.56

  Impact points

  ADF/n-cofilin-dependent actin turnover determines platelet formation and sizing.

  Markus Bender, Anita Eckly, John H Hartwig, Margitta Elvers, Irina Pleines, Shuchi Gupta, Georg Krohne, Elisabeth Jeanclos, Antje Gohla, Christine Gurniak, Christian Gachet, Walter Witke, Bernhard Nieswandt

  Blood. 09/2010; 116(10):1767-75.

  The cellular and molecular mechanisms orchestrating the complex process by which bone marrow megakaryocytes form and release platelets remain poorly understood. Mature megakaryocytes generate long cytoplasmic extensions, proplatelets, which have the capacity to generate platelets. Although microtubu... [more] The cellular and molecular mechanisms orchestrating the complex process by which bone marrow megakaryocytes form and release platelets remain poorly understood. Mature megakaryocytes generate long cytoplasmic extensions, proplatelets, which have the capacity to generate platelets. Although microtubules are the main structural component of proplatelets and microtubule sliding is known to drive proplatelet elongation, the role of actin dynamics in the process of platelet formation has remained elusive. Here, we tailored a mouse model lacking all ADF/n-cofilin-mediated actin dynamics in megakaryocytes to specifically elucidate the role of actin filament turnover in platelet formation. We demonstrate, for the first time, that in vivo actin filament turnover plays a critical role in the late stages of platelet formation from megakaryocytes and the proper sizing of platelets in the periphery. Our results provide the genetic proof that platelet production from megakaryocytes strictly requires dynamic changes in the actin cytoskeleton.