Dual role for CXCL12 signaling in semilunar valve development
Summary: Cxcl12-null embryos have dysplastic, misaligned, and hyperplastic semilunar valves (SLVs). In this study, we show that CXCL12 signaling via its receptor CXCR4 fulfills distinct roles at different stages of SLV development, acting initially as a guidance cue to pattern cellular distribution...
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2021-08-01
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doaj-b27f1fd78c4b48318d3f134c2b6b8a852021-08-26T04:33:29ZengElsevierCell Reports2211-12472021-08-01368109610Dual role for CXCL12 signaling in semilunar valve developmentLiam A. Ridge0Dania Kewbank1Dagmar Schütz2Ralf Stumm3Peter J. Scambler4Sarah Ivins5Developmental Biology of Birth Defects, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UKDevelopmental Biology of Birth Defects, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UKInstitute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, GermanyInstitute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, GermanyDevelopmental Biology of Birth Defects, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UKDevelopmental Biology of Birth Defects, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK; Corresponding authorSummary: Cxcl12-null embryos have dysplastic, misaligned, and hyperplastic semilunar valves (SLVs). In this study, we show that CXCL12 signaling via its receptor CXCR4 fulfills distinct roles at different stages of SLV development, acting initially as a guidance cue to pattern cellular distribution within the valve primordia during the endocardial-to-mesenchymal transition (endoMT) phase and later regulating mesenchymal cell proliferation during SLV remodeling. Transient, anteriorly localized puncta of internalized CXCR4 are observed in cells undergoing endoMT. In vitro, CXCR4+ cell orientation in response to CXCL12 requires phosphatidylinositol 3-kinase (PI3K) signaling and is inhibited by suppression of endocytosis. This dynamic intracellular localization of CXCR4 during SLV development is related to CXCL12 availability, potentially enabling activation of divergent downstream signaling pathways at key developmental stages. Importantly, Cxcr7-/- mutants display evidence of excessive CXCL12 signaling, indicating a likely role for atypical chemokine receptor CXCR7 in regulating ligand bioavailability and thus CXCR4 signaling output during SLV morphogenesis.http://www.sciencedirect.com/science/article/pii/S2211124721010482cell migrationCXCL12CXCR4CXCR7outflow tractsemilunar valves |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Liam A. Ridge Dania Kewbank Dagmar Schütz Ralf Stumm Peter J. Scambler Sarah Ivins |
spellingShingle |
Liam A. Ridge Dania Kewbank Dagmar Schütz Ralf Stumm Peter J. Scambler Sarah Ivins Dual role for CXCL12 signaling in semilunar valve development Cell Reports cell migration CXCL12 CXCR4 CXCR7 outflow tract semilunar valves |
author_facet |
Liam A. Ridge Dania Kewbank Dagmar Schütz Ralf Stumm Peter J. Scambler Sarah Ivins |
author_sort |
Liam A. Ridge |
title |
Dual role for CXCL12 signaling in semilunar valve development |
title_short |
Dual role for CXCL12 signaling in semilunar valve development |
title_full |
Dual role for CXCL12 signaling in semilunar valve development |
title_fullStr |
Dual role for CXCL12 signaling in semilunar valve development |
title_full_unstemmed |
Dual role for CXCL12 signaling in semilunar valve development |
title_sort |
dual role for cxcl12 signaling in semilunar valve development |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2021-08-01 |
description |
Summary: Cxcl12-null embryos have dysplastic, misaligned, and hyperplastic semilunar valves (SLVs). In this study, we show that CXCL12 signaling via its receptor CXCR4 fulfills distinct roles at different stages of SLV development, acting initially as a guidance cue to pattern cellular distribution within the valve primordia during the endocardial-to-mesenchymal transition (endoMT) phase and later regulating mesenchymal cell proliferation during SLV remodeling. Transient, anteriorly localized puncta of internalized CXCR4 are observed in cells undergoing endoMT. In vitro, CXCR4+ cell orientation in response to CXCL12 requires phosphatidylinositol 3-kinase (PI3K) signaling and is inhibited by suppression of endocytosis. This dynamic intracellular localization of CXCR4 during SLV development is related to CXCL12 availability, potentially enabling activation of divergent downstream signaling pathways at key developmental stages. Importantly, Cxcr7-/- mutants display evidence of excessive CXCL12 signaling, indicating a likely role for atypical chemokine receptor CXCR7 in regulating ligand bioavailability and thus CXCR4 signaling output during SLV morphogenesis. |
topic |
cell migration CXCL12 CXCR4 CXCR7 outflow tract semilunar valves |
url |
http://www.sciencedirect.com/science/article/pii/S2211124721010482 |
work_keys_str_mv |
AT liamaridge dualroleforcxcl12signalinginsemilunarvalvedevelopment AT daniakewbank dualroleforcxcl12signalinginsemilunarvalvedevelopment AT dagmarschutz dualroleforcxcl12signalinginsemilunarvalvedevelopment AT ralfstumm dualroleforcxcl12signalinginsemilunarvalvedevelopment AT peterjscambler dualroleforcxcl12signalinginsemilunarvalvedevelopment AT sarahivins dualroleforcxcl12signalinginsemilunarvalvedevelopment |
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1721196150528147456 |