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

Research output: Contribution to journalArticlepeer-review

Standard

Podoplanin and CLEC-2 drive cerebrovascular patterning and integrity during development. / Lowe, Kate L; Finney, Brenda A; Deppermann, Carsten; Hägerling, René; Gazit, Salomé L; Frampton, Jonathan; Buckley, Christopher; Camerer, Eric; Nieswandt, Bernhard; Kiefer, Friedemann; Watson, Steve P.

In: Blood, Vol. 125, No. 24, 11.06.2015, p. 3769-3777.

Research output: Contribution to journalArticlepeer-review

Harvard

APA

Vancouver

Author

Lowe, Kate L ; Finney, Brenda A ; Deppermann, Carsten ; Hägerling, René ; Gazit, Salomé L ; Frampton, Jonathan ; Buckley, Christopher ; Camerer, Eric ; Nieswandt, Bernhard ; Kiefer, Friedemann ; Watson, Steve P. / Podoplanin and CLEC-2 drive cerebrovascular patterning and integrity during development. In: Blood. 2015 ; Vol. 125, No. 24. pp. 3769-3777.

Bibtex

@article{c5460bf503454424bb2367bd2ba4982f,
title = "Podoplanin and CLEC-2 drive cerebrovascular patterning and integrity during development",
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.",
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",
author = "Lowe, {Kate L} and Finney, {Brenda A} and Carsten Deppermann and Ren{\'e} H{\"a}gerling and Gazit, {Salom{\'e} L} and Jonathan Frampton and Christopher Buckley and Eric Camerer and Bernhard Nieswandt and Friedemann Kiefer and Watson, {Steve P}",
note = "{\textcopyright} 2015 by The American Society of Hematology.",
year = "2015",
month = jun,
day = "11",
doi = "10.1182/blood-2014-09-603803",
language = "English",
volume = "125",
pages = "3769--3777",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "24",

}

RIS

TY - JOUR

T1 - Podoplanin and CLEC-2 drive cerebrovascular patterning and integrity during development

AU - Lowe, Kate L

AU - Finney, Brenda A

AU - Deppermann, Carsten

AU - Hägerling, René

AU - Gazit, Salomé L

AU - Frampton, Jonathan

AU - Buckley, Christopher

AU - Camerer, Eric

AU - Nieswandt, Bernhard

AU - Kiefer, Friedemann

AU - Watson, Steve P

N1 - © 2015 by The American Society of Hematology.

PY - 2015/6/11

Y1 - 2015/6/11

N2 - 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.

AB - 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.

KW - Animals

KW - Blood Platelets

KW - Body Patterning

KW - Brain

KW - Cerebrovascular Circulation

KW - Gene Deletion

KW - Gene Expression Regulation, Developmental

KW - Intracranial Hemorrhages

KW - Lectins, C-Type

KW - Membrane Glycoproteins

KW - Mice, Inbred C57BL

KW - Platelet Activation

KW - Platelet Aggregation

KW - Platelet Membrane Glycoprotein IIb

U2 - 10.1182/blood-2014-09-603803

DO - 10.1182/blood-2014-09-603803

M3 - Article

C2 - 25908104

VL - 125

SP - 3769

EP - 3777

JO - Blood

JF - Blood

SN - 0006-4971

IS - 24

ER -