Dual role for CXCL12 signaling in semilunar valve development

RIDGE, Liam, KEWBANK, Dania, SCHÜTZ, Dagmar, STUMM, Ralf, SCAMBLER, Peter J and IVINS, Sarah (2021). Dual role for CXCL12 signaling in semilunar valve development. Cell Reports, 36 (8): 109610.

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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.

Item Type:	Article
Uncontrolled Keywords:	0601 Biochemistry and Cell Biology; 1116 Medical Physiology; 31 Biological sciences
Identification Number:	https://doi.org/10.1016/j.celrep.2021.109610
SWORD Depositor:	Symplectic Elements
Depositing User:	Symplectic Elements
Date Deposited:	15 Jun 2023 15:13
Last Modified:	11 Oct 2023 14:01
URI:	https://shura.shu.ac.uk/id/eprint/31584

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