Ridge, LA;
Kewbank, D;
Schuetz, D;
Stumm, R;
Scambler, PJ;
Ivins, S;
(2021)
Dual role for CXCL12 signaling in semilunar valve development.
Cell Reports
, 36
(8)
, Article 109610. 10.1016/j.celrep.2021.109610.
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Abstract
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.
Type: | Article |
---|---|
Title: | Dual role for CXCL12 signaling in semilunar valve development |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1016/j.celrep.2021.109610 |
Publisher version: | http://dx.doi.org/10.1016/j.celrep.2021.109610 |
Language: | English |
Additional information: | © 2021 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) |
Keywords: | NEURAL CREST CELLS, C-TERMINAL TAIL, CHEMOKINE RECEPTOR, BETA-ARRESTIN, TISSUE MIGRATION, OUTFLOW TRACT, CXCR4, HEART, PHOSPHORYLATION, INTERNALIZATION, CXCL12, CXCR4, CXCR7, cell migration |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
URI: | https://discovery.ucl.ac.uk/id/eprint/10134036 |
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