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Heightened activation of embryonic megakaryocytes causes aneurysms in the developing brain of mice lacking podoplanin
Christopher Hoover1,2, Yuji Kondo1, Bojing Shao1
1Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.
Abstract:
During early embryonic development in mammals, including humans and mice, megakaryocytes (Mks) first originate from primitive hematopoiesis in the yolk sac. These embryonic Mks (eMks) circulate in the vasculature with unclear function. Herein, we report that podoplanin (PDPN), the ligand of C-type lectin-like receptor (CLEC-2) on Mks/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 the lower diencephalon in mutant mouse embryos than in wild-type littermates before hemorrhage. We found that PDPN counteracted the collagen-1-induced secretion of angiopoietin-1 from fetal Mks, which coincided with enhanced TIE-2 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.
Insights
Podoplanin (PDPN) on embryonic megakaryocytes (eMks) regulates vascular development. Loss of PDPN causes hemorrhage in developing mouse brains, revealing a crucial role for eMks in midgestation vascular integrity.
Area of Science:
- Developmental Biology
- Hematology
- Neuroscience
Background:
- Embryonic megakaryocytes (eMks) originate from primitive hematopoiesis in the yolk sac.
- The function of circulating eMks during mammalian embryonic development remains largely unclear.
- Podoplanin (PDPN), a ligand for C-type lectin-like receptor 2 (CLEC-2), is expressed on Mks/platelets.
Purpose of the Study:
- To investigate the role of PDPN in embryonic megakaryocyte (eMk) function during mammalian development.
- To determine the consequences of PDPN or CLEC-2 deficiency on embryonic vascular development.
- To elucidate the mechanism by which PDPN regulates eMk-mediated vascular integrity.
Main Methods:
- Analysis of mouse embryos with genetic deficiencies in PDPN or CLEC-2.
- Immunohistochemical analysis of PDPN expression in neural tissue during midgestation.
- Assessment of eMk/platelet localization, granule release, and vascular morphology.
- Investigation of angiopoietin-1 secretion and TIE-2 activation in fetal Mks.
- In vivo experiments blocking platelet activation.
Main Results:
- Loss of PDPN or CLEC-2 led to aneurysms and spontaneous hemorrhage in the lower diencephalon of midgestation mouse embryos.
- eMks/platelets showed enhanced granule release and preferential localization to the lower diencephalon in mutant embryos prior to hemorrhage.
- PDPN was found to counteract collagen-1-induced angiopoietin-1 secretion from fetal Mks.
- PDPN deficiency correlated with enhanced TIE-2 activation in vascular sprouts, and blocking platelet activation prevented vascular defects.
Conclusions:
- PDPN plays a critical role in regulating embryonic megakaryocyte (eMk) function during midgestation.
- The PDPN-CLEC-2 axis is essential for preventing vascular abnormalities, such as hemorrhage, in the developing brain.
- This study reveals a novel function for PDPN in maintaining vascular integrity through modulation of eMk activity.
