Multiple alterations of platelet functions dominated by increased secretion in mice lacking Cdc42 in platelets

TY - JOUR

T1 - Multiple alterations of platelet functions dominated by increased secretion in mice lacking Cdc42 in platelets

AU - Pleines, Irina

AU - Eckly, Anita

AU - Elvers, Margitta

AU - Hagedorn, Ina

AU - Eliautou, Sandra

AU - Bender, Markus

AU - Wu, Xunwei

AU - Lanza, Francois

AU - Gachet, Christian

AU - Brakebusch, Cord

AU - Nieswandt, Bernhard

N1 - Keywords: Animals; Blood Platelets; Blotting, Western; Cell Separation; Flow Cytometry; GTP-Binding Protein Regulators; Hemostasis; Mice; Mice, Knockout; Microscopy, Electron; Platelet Activation

PY - 2010/4/22

Y1 - 2010/4/22

N2 - Platelet activation at sites of vascular injury is crucial for hemostasis, but it may also cause myocardial infarction or stroke. Cytoskeletal reorganization is essential for platelet activation and secretion. The small GTPase Cdc42 has been implicated as an important mediator of filopodia formation and exocytosis in various cell types, but its exact function in platelets is not established. Here, we show that the megakaryocyte/platelet-specific loss of Cdc42 leads to mild thrombocytopenia and a small increase in platelet size in mice. Unexpectedly, Cdc42-deficient platelets were able to form normally shaped filopodia and spread fully on fibrinogen upon activation, whereas filopodia formation upon selective induction of GPIb signaling was reduced compared with wild-type platelets. Furthermore, Cdc42-deficient platelets showed enhanced secretion of α granules, a higher adenosine diphosphate (ADP)/adenosine triphosphate (ATP) content, increased aggregation at low agonist concentrations, and enhanced aggregate formation on collagen under flow. In vivo, lack of Cdc42 resulted in faster occlusion of ferric chloride-injured arterioles. The life span of Cdc42-deficient platelets was markedly reduced, suggesting increased clearing of the cells under physiologic conditions. These data point to novel multiple functions of Cdc42 in the regulation of platelet activation, granule organization, degranulation, and a specific role in GPIb signaling.

AB - Platelet activation at sites of vascular injury is crucial for hemostasis, but it may also cause myocardial infarction or stroke. Cytoskeletal reorganization is essential for platelet activation and secretion. The small GTPase Cdc42 has been implicated as an important mediator of filopodia formation and exocytosis in various cell types, but its exact function in platelets is not established. Here, we show that the megakaryocyte/platelet-specific loss of Cdc42 leads to mild thrombocytopenia and a small increase in platelet size in mice. Unexpectedly, Cdc42-deficient platelets were able to form normally shaped filopodia and spread fully on fibrinogen upon activation, whereas filopodia formation upon selective induction of GPIb signaling was reduced compared with wild-type platelets. Furthermore, Cdc42-deficient platelets showed enhanced secretion of α granules, a higher adenosine diphosphate (ADP)/adenosine triphosphate (ATP) content, increased aggregation at low agonist concentrations, and enhanced aggregate formation on collagen under flow. In vivo, lack of Cdc42 resulted in faster occlusion of ferric chloride-injured arterioles. The life span of Cdc42-deficient platelets was markedly reduced, suggesting increased clearing of the cells under physiologic conditions. These data point to novel multiple functions of Cdc42 in the regulation of platelet activation, granule organization, degranulation, and a specific role in GPIb signaling.

U2 - 10.1182/blood-2009-09-242271

DO - 10.1182/blood-2009-09-242271

M3 - Journal article

C2 - 20139097

SN - 0006-4971

VL - 115

SP - 3364

EP - 3373

JO - Blood

JF - Blood

IS - 16

ER -