Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling.
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.
Bertozzi
Cara C
CC
Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd., Philadelphia, PA 19104, USA.
Schmaier
Alec A
AA
Mericko
Patricia
P
Hess
Paul R
PR
Zou
Zhiying
Z
Chen
Mei
M
Chen
Chiu-Yu
CY
Xu
Bin
B
Lu
Min-min
MM
Zhou
Diane
D
Sebzda
Eric
E
Santore
Matthew T
MT
Merianos
Demetri J
DJ
Stadtfeld
Matthias
M
Flake
Alan W
AW
Graf
Thomas
T
Skoda
Radek
R
Maltzman
Jonathan S
JS
Koretzky
Gary A
GA
Kahn
Mark L
ML
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000502:physiology*; D001808:Blood Vessels / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D004729:Endothelium, Lymphatic / Q000196:embryology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000196:embryology / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D042601:Lymphatic Vessels / Q000196:embryology* / Q000378:metabolism / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000098853:Podoplanin
D048868:Adaptor Proteins, Signal Transducing; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; C529518:CLEC-2 protein, mouse; C490441:Pdpn protein, mouse; D000098853:Podoplanin; C092947:SLP-76 signal Transducing adaptor proteins