期刊
DEVELOPMENT
卷 140, 期 16, 页码 3395-3402出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.097360
关键词
Bone morphogenetic protein; microRNA; Vascular endothelial growth factor A; Epithelial to mesenchymal transition; Outflow tract; Mouse
资金
- National Institutes of Health [R01HL093484, R01DE12324]
- Vivian L. Smith Foundation
- American Heart Association Southwest Affiliate Predoctoral Fellowship [12PRE11720003]
- American Heart Association Scientist Development Grant [0930240N]
- Heart Rhythm Society
Congenital heart disease (CHD) is a devastating anomaly that affects similar to 1% of live births. Defects of the outflow tract (OFT) make up a large percentage of human CHD. We investigated Bmp signaling in mouse OFT development by conditionally deleting both Bmp4 and Bmp7 in the second heart field (SHF). SHF Bmp4/7 deficiency resulted in defective epithelial to mesenchymal transition (EMT) and reduced cardiac neural crest ingress, with resultant persistent truncus arteriosus. Using a candidate gene approach, we found that Vegfa was upregulated in the Bmp4/7 mutant hearts. To determine if Vegfa is a downstream Bmp effector during EMT, we examined whether Vegfa is transcriptionally regulated by the Bmp receptor-regulated Smad. Our findings indicate that Smad directly binds to Vegfa chromatin and represses Vegfa transcriptional activity. We also found that Vegfa is a direct target for the miR-17-92 cluster, which is also regulated by Bmp signaling in the SHF. Deletion of miR-17-92 reveals similar phenotypes to Bmp4/7 SHF deletion. To directly address the function of Vegfa repression in Bmp-mediated EMT, we performed ex vivo explant cultures from Bmp4/7 and miR-17-92 mutant hearts. EMT was defective in explants from the Bmp4/7 double conditional knockout (dCKO; Mef2c-Cre; Bmp4/7f/f) and miR-17-92 null. By antagonizing Vegfa activity in explants, EMT was rescued in Bmp4/7 dCKO and miR-17-92 null culture. Moreover, overexpression of miR-17-92 partially suppressed the EMT defect in Bmp4/7 mutant embryos. Our study reveals that Vegfa levels in the OFT are tightly controlled by Smad-and microRNA-dependent pathways to modulate OFT development.
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