Key Points

  • Activated embryonic megakaryocytes/platelets cause aneurysm formation in developing brains of mice lacking podoplanin

  • Podoplanin lessens collagen I-induced secretion of angiopoietin-1 from eMks, preventing detrimental TIE2 activation in sprouting endothelium

During early embryonic development in mammals, including humans and mice, megakaryocytes first originate from primitive hematopoiesis in the yolk sac. These embryonic megakaryocytes (eMk) circulate in the vasculature with unclear function. Here we report that podoplanin (PDPN), the ligand of C-type lectin-like receptor (CLEC-2) on megakaryocytes/platelets, is temporarily expressed in neural tissue during midgestation in mice. Loss of PDPN or CLEC-2 resulted in aneurysms and spontaneous hemorrhage specifically in the lower diencephalon during midgestation. Surprisingly, more eMks/platelets had enhanced granule release and localized to lower diencephalon in mutant mouse embryos than wild-type littermates prior to hemorrhage. We found that PDPN counteracted the collagen I-induced secretion of angiopoietin-1 from fetal megakaryocytes, which coincided with enhanced TIE2 activation in aneurysm-like sprouts of PDPN-deficient embryos. Blocking platelet activation prevented the PDPN-deficient embryo from developing vascular defects. Our data reveal a new role for PDPN in regulating eMk function during midgestation.

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