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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2016 (publ. 2015, arch)     Display Documents



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ID: 717292.0, MPI für molekulare Biomedizin / Jahrbuch 2016 (publ. 2015, arch)
Podoplanin and CLEC-2 drive cerebrovascular patterning and integrity during development
Authors:Lowe, K. L.; Finney, B. A.; Deppermann, C.; Hagerling, R.; Gazit, S. L.; Frampton, J.; Buckley, C.; Camerer, E.; Nieswandt, B.; Kiefer, F.; Watson, S. P.
Date of Publication (YYYY-MM-DD):2015-06-11
Title of Journal:Blood
Volume:125
Issue / Number:24
Start Page:3769
End Page:3777
Review Status:Internal review
Audience:Not Specified
Abstract / Description: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 alpha-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.
Free Keywords:Animals; Blood Platelets/metabolism; Body Patterning; Brain/*blood supply/*embryology/metabolism; *Cerebrovascular Circulation; Gene Deletion; Gene Expression Regulation, Developmental; Intracranial Hemorrhages/genetics/metabolism; Lectins, C-Type/*genetics/metabolism; Membrane Glycoproteins/*genetics/metabolism; Mice, Inbred C57BL; Platelet Activation; Platelet Aggregation; Platelet Membrane Glycoprotein IIb/genetics/metabolism
External Publication Status:published
Document Type:Article
Communicated by:Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Department of Experimental Biomedicine, University of Wurzburg, University Hospital and Rudolf Virchow Centre, Wurzburg, Germany; Max-Planck-Institute for Molecular Biomedicine, Department Vascular Cell Biology, Munster, Germany; INSERM U970, Paris Cardiovascular Research Centre, Paris, France; Universite Paris-Descartes, Paris, France; School of Immunity and Infection, and. Rheumatology Research Group, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Identifiers:ISSN:1528-0020 (Electronic) 0006-4971 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/25908104 [ID No:2]
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