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Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling

Cara C. Bertozzi, Alec A. Schmaier, Patricia Mericko, Paul R. Hess, Zhiying Zou, Mei Chen, Chiu-Yu Chen, Bin Xu, Min-min Lu, Diane Zhou, Eric Sebzda, Matthew T. Santore, Demetri J. Merianos, Matthias Stadtfeld, Alan W. Flake, Thomas Graf, Radek Skoda, Jonathan S. Maltzman, Gary A. Koretzky and Mark L. Kahn

Abstract

Although platelets appear by E10.5 in the developing mouse, an embryonic role for these cells has not been identified. The SYK-SLP-76 signaling pathway is required in blood cells to regulate embryonic blood-lymphatic vascular separation, but the cell type and molecular mechanism underlying this regulatory pathway is not known. In the present study we demonstrate that platelets regulate lymphatic vascular development by directly interacting with lymphatic endothelial cells through CLEC-2 receptors. PODOPLANIN (PDPN), a transmembrane protein expressed on the surface of lymphatic endothelial cells, is required in non-hematopoietic cells for blood-lymphatic separation. Genetic loss of the PDPN receptor CLEC-2 ablates PDPN binding by platelets and confers embryonic lymphatic vascular defects like those seen in animals lacking PDPN or SLP-76. PF4-Cre mediated deletion of Slp-76 is sufficient to confer lymphatic vascular defects, identifying platelets as the cell type in which SLP-76 signaling is required to regulate lymphatic vascular development. Consistent with these genetic findings, we observe SLP-76-dependent platelet aggregate formation on the surface of lymphatic endothelial cells in vivo and ex vivo. These studies identify a non-hemostatic pathway in which platelet CLEC-2 receptors bind lymphatic endothelial PDPN and activate SLP-76 signaling to regulate embryonic vascular development.

  • Submitted February 23, 2010.
  • Accepted March 24, 2010.