The Journal of Experimental Medicine
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Published online December 17, 2007
doi:10.1084/jem.20071800
The Journal of Experimental Medicine, Vol. 204, No. 13, 3103-3111
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Petrich et al.
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BRIEF DEFINITIVE REPORT

 Talin is required for integrin-mediated platelet function in hemostasis and thrombosis

Brian G. Petrich1, Patrizia Marchese2, Zaverio M. Ruggeri2, Saskia Spiess1, Rachel A.M. Weichert1, Feng Ye1, Ralph Tiedt3, Radek C. Skoda3, Susan J. Monkley4, David R. Critchley4, and Mark H. Ginsberg1

1 Department of Medicine, University of California, San Diego, La Jolla, CA 92093
2 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037
3 Department of Experimental Hematology, University Hospital Basel, 4031 Basel, Switzerland
4 Department of Biochemistry, Henry Wellcome Building, University of Leicester, Leicester LE1 9HN, UK

CORRESPONDENCE Mark H. Ginsberg: mhginsberg{at}ucsd.edu

Integrins are critical for hemostasis and thrombosis because they mediate both platelet adhesion and aggregation. Talin is an integrin-binding cytoplasmic adaptor that is a central organizer of focal adhesions, and loss of talin phenocopies integrin deletion in Drosophila. Here, we have examined the role of talin in mammalian integrin function in vivo by selectively disrupting the talin1 gene in mouse platelet precursor megakaryocytes. Talin null megakaryocytes produced circulating platelets that exhibited normal morphology yet manifested profoundly impaired hemostatic function. Specifically, platelet-specific deletion of talin1 led to spontaneous hemorrhage and pathological bleeding. Ex vivo and in vitro studies revealed that loss of talin1 resulted in dramatically impaired integrin {alpha}IIbβ3-mediated platelet aggregation and β1 integrin–mediated platelet adhesion. Furthermore, loss of talin1 strongly inhibited the activation of platelet β1 and β3 integrins in response to platelet agonists. These data establish that platelet talin plays a crucial role in hemostasis and provide the first proof that talin is required for the activation and function of mammalian {alpha}2β1 and {alpha}IIbβ3 integrins in vivo.


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