Podoplanin and CLEC-2 drive cerebrovascular patterning and integrity during development

Research output: Contribution to journalArticle

Authors

  • Carsten Deppermann
  • René Hägerling
  • Salomé L Gazit
  • Eric Camerer
  • Bernhard Nieswandt
  • Friedemann Kiefer

Abstract

Mice with a constitutive or platelet-specific deletion of the C-type-lectin-like receptor (CLEC-2) exhibit hemorrhaging in the brain at mid-gestation. We sought to investigate the basis of this defect, hypothesizing that it is mediated by the loss of CLEC-2 activation by its endogenous ligand, podoplanin, which is expressed on the developing neural tube. To induce deletion of podoplanin at the 2-cell stage, we generated a podoplanin(fl/fl) mouse crossed to a PGK-Cre mouse. Using 3-dimensional light-sheet microscopy, we observed cerebral vessels were tortuous and aberrantly patterned at embryonic (E) day 10.5 in podoplanin- and CLEC-2-deficient mice, preceding the formation of large hemorrhages throughout the fore-, mid-, and hindbrain by E11.5. Immunofluorescence and electron microscopy revealed defective pericyte recruitment and misconnections between the endothelium of developing blood vessels and surrounding pericytes and neuro-epithelial cells. Nestin-Cre-driven deletion of podoplanin on neural progenitors also caused widespread cerebral hemorrhaging. Hemorrhaging was also seen in the ventricles of embryos deficient in the platelet integrin subunit glycoprotein IIb or in embryos in which platelet α-granule and dense granule secretion is abolished. We propose a novel role for podoplanin on the neuro-epithelium, which interacts with CLEC-2 on platelets, mediating platelet adhesion, aggregation, and secretion to guide the maturation and integrity of the developing vasculature and prevent hemorrhage.

Bibliographic note

© 2015 by The American Society of Hematology.

Details

Original languageEnglish
Pages (from-to)3769-3777
Number of pages9
JournalBlood
Volume125
Issue number24
Publication statusPublished - 11 Jun 2015

Keywords

  • Animals, Blood Platelets, Body Patterning, Brain, Cerebrovascular Circulation, Gene Deletion, Gene Expression Regulation, Developmental, Intracranial Hemorrhages, Lectins, C-Type, Membrane Glycoproteins, Mice, Inbred C57BL, Platelet Activation, Platelet Aggregation, Platelet Membrane Glycoprotein IIb