Multiple alterations of platelet functions dominated by increased secretion in mice lacking Cdc42 in platelets.
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 alpha 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.
Pleines
Irina
I
Department of Vascular Medicine, University Clinic, University of Würzburg and Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Würzburg, Germany.
Eckly
Anita
A
Elvers
Margitta
M
Hagedorn
Ina
I
Eliautou
Sandra
S
Bender
Markus
M
Wu
Xunwei
X
Lanza
Francois
F
Gachet
Christian
C
Brakebusch
Cord
C
Nieswandt
Bernhard
B
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000648:ultrastructure*; D015153:Blotting, Western; D002469:Cell Separation; D005434:Flow Cytometry; D020555:GTP-Binding Protein Regulators / Q000172:deficiency*; D006487:Hemostasis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D015539:Platelet Activation / Q000502:physiology*
C484092:Cdc42ep5 protein, mouse; D020555:GTP-Binding Protein Regulators