Abstract
SummaryCxcl12-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.
Highlights
The semilunar valves (SLVs) are positioned at the base of the great arteries and ensure unidirectional blood flow (O’Donnell and Yutzey, 2020; Spicer et al, 2014)
Whole-mount and section immunostaining with PECAM-1 antibody confirmed that aortic valve (AoV) and pulmonary valve (PV) leaflets in Cxcl12 nulls were severely affected at E15.5, with failure of coaptation (Figures 1A–1D)
Total SLV volume was increased in Cxcl12 nulls (1.5-fold in the PV and 1.3-fold in the AoV), this was only significant for the PV (Figures 1M and 1N)
Summary
The semilunar valves (SLVs) are positioned at the base of the great arteries and ensure unidirectional blood flow (O’Donnell and Yutzey, 2020; Spicer et al, 2014). Fusion of the main cushions and septation of the OFT give rise to the tricuspid SLVs by E12.5 (Combs and Yutzey, 2009; Lin et al, 2012). Neural crest (NC) contributes substantially to the main OFT cushions (de Lange et al, 2004; Liu et al, 2018; Nakamura et al, 2006; Phillips et al, 2013), the intercalated cushions have been shown to originate largely from second heart field (SHF) (Eley et al, 2018; Sizarov et al, 2012). Sculpting and specification of valve primordia into mature leaflets with stratified extracellular matrix (ECM) is directed by both proliferation and differentiation of mesenchymal cells (Combs and Yutzey, 2009; Lin et al, 2012; MacGrogan et al, 2014; O’Donnell and Yutzey, 2020) and regulated, at least in part, by hemodynamic forces (Goddard et al, 2017; Hsu et al, 2019)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
