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

Blood. 2010 Jul 29;116(4):661-70. doi: 10.1182/blood-2010-02-270876. Epub 2010 Apr 2.

Abstract

Although platelets appear by embryonic day 10.5 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 are not known. In the present study we demonstrate that platelets regulate lymphatic vascular development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2 (CLEC-2) receptors. PODOPLANIN (PDPN), a transmembrane protein expressed on the surface of lymphatic endothelial cells, is required in nonhematopoietic 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. Platelet factor 4-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 nonhemostatic pathway in which platelet CLEC-2 receptors bind lymphatic endothelial PDPN and activate SLP-76 signaling to regulate embryonic vascular development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Blood Platelets / metabolism
  • Blood Platelets / physiology*
  • Blood Vessels / metabolism
  • Cells, Cultured
  • Embryo, Mammalian
  • Endothelial Cells / metabolism
  • Endothelial Cells / physiology
  • Endothelium, Lymphatic / embryology
  • Endothelium, Lymphatic / metabolism
  • Endothelium, Vascular / embryology
  • Endothelium, Vascular / metabolism
  • Humans
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism
  • Lectins, C-Type / physiology*
  • Lymphatic Vessels / embryology*
  • Lymphatic Vessels / metabolism
  • Lymphatic Vessels / physiology*
  • Membrane Glycoproteins / metabolism
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphoproteins / physiology*
  • Protein Binding
  • Signal Transduction / genetics
  • Signal Transduction / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • CLEC-2 protein, mouse
  • Gp38 protein, mouse
  • Lectins, C-Type
  • Membrane Glycoproteins
  • Phosphoproteins
  • SLP-76 signal Transducing adaptor proteins