Journal
DEVELOPMENTAL BIOLOGY
Volume 441, Issue 1, Pages 42-51Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ydbio.2018.05.024
Keywords
Coronary artery; Secondary heart field; Endothelial proliferation; R-spondin3 (Rspo3); Wnt signaling; Leucine Rich Repeat G Protein coupled; receptor (Lgr4)
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Funding
- Fondation du France, ARC [SL22020605297]
- ANR (ANR-ADSTEM) [ANR-11-LABX-0028-01]
- National Institutes of Health [IR01HL131735, 1R56HL129807]
- American Heart Association [15GRNT25710153]
- Agence Nationale de la Recherche (ANR) [ANR-11-LABX-0028] Funding Source: Agence Nationale de la Recherche (ANR)
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Coronary artery anomalies are common congenital disorders with serious consequences in adult life. Coronary circulation begins when the coronary stems form connections between the aorta and the developing vascular plexus. We recently identified the WNT signaling modulator R-spondin 3 (Rspo3), as a crucial regulator of coronary stem proliferation. Using expression analysis and tissue-specific deletion we now demonstrate that Rspo3 is primarily produced by cardiomyocytes. Moreover, we have employed CRISPR/Cas9 technology to generate novel Lgr4-null alleles that showed a significant decrease in coronary stem proliferation and thus phenocopied the coronary artery defects seen in Rspo3 mutants. Interestingly, Lgr4 mutants displayed slightly hypomorphic right ventricles, an observation also made after myocardial specific deletion of Rspo3. These results shed new light on the role of Rspo3 in heart development and demonstrate that LGR4 is the principal Rspondin 3 receptor in the heart.
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