Over-expression of Fgf8 in cardiac neural crest cells leads to persistent truncus arteriosus
- 5 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Molecular Histology
- Vol. 52 (2), 351-361
- https://doi.org/10.1007/s10735-021-09956-2
Abstract
During cardiogenesis, the outflow tract undergoes a complicated morphogenesis, including the re-alignment of the great blood vessels, and the separation of aorta and pulmonary trunk. The deficiency of FGF8 in the morphogenesis of outflow tract has been well studied, however, the effect of over-dosed FGF8 on the development of outflow tract remains unknown. In this study, Rosa26R-Fgf8 knock-in allele was constitutively activated by Wnt1-cre transgene in the mouse neural crest cells presumptive for the endocardial cushion of outflow tract. Surprisingly, Wnt1-cre; Rosa26R-Fgf8 mouse embryos exhibited persistent truncus arteriosus and died prior to E15.5. The cardiac neural crest cells in Wnt1-cre; Rosa26R-Fgf8 truncus arteriosus did not degenerate as in WT controls, but proliferated into a thickened endocardial cushion and then, blocked the blood outflow from cardiac chambers into the lungs, which resulted in the embryonic lethality. Although the spiral aorticopulmonary septum failed to form, the differentiaion of the endothelium and smooth muscle in the Wnt1-cre; Rosa26R-Fgf8 truncus arteriosus were impacted little. However, lineage tracing assay showed that the neural crest derived cells aggregated in the cushion layer, but failed to differentiate into the endothelium of Wnt1-cre; Rosa26R-Fgf8 truncus arteriosus. Further investigation displayed the reduced p-Akt and p-Erk immunostaining, and the decreased Bmp2 and Bmp4 transcription in the endothelium of Wnt1-cre; Rosa26R-Fgf8 truncus arteriosus. Our findings suggested that Fgf8 over-expression in cardiac neural crest impaired the formation of aorticopulmonary septum by suppressing the endothelial differentiation and stimulating the proliferation of endocardial cushion cells, which implicated a novel etiology of persistent truncus arteriosus.Keywords
Funding Information
- National Natural Science Foundation of China (81771055, 81970922)
This publication has 43 references indexed in Scilit:
- Delineating a Conserved Genetic Cassette Promoting Outgrowth of Body AppendagesPLoS Genetics, 2013
- Coordinating Tissue Interactions: Notch Signaling in Cardiac Development and DiseaseDevelopmental Cell, 2012
- FGF8 signaling is chemotactic for cardiac neural crest cellsDevelopmental Biology, 2011
- Trigenic neural crest-restricted Smad7 over-expression results in congenital craniofacial and cardiovascular defectsDevelopmental Biology, 2010
- The Bax/Bak ortholog inDrosophila, Debcl, exerts limited control over programmed cell deathDevelopment, 2009
- An FGF autocrine loop initiated in second heart field mesoderm regulates morphogenesis at the arterial pole of the heartDevelopment, 2008
- Smad signaling in the neural crest regulates cardiac outflow tract remodeling through cell autonomous and non-cell autonomous effectsDevelopmental Biology, 2007
- Model systems for the study of heart development and disease: Cardiac neural crest and conotruncal malformationsSeminars in Cell & Developmental Biology, 2007
- Required, tissue-specific roles for Fgf8 in outflow tract formation and remodelingDevelopment, 2006
- Bmp4 signaling is required for outflow-tract septation and branchial-arch artery remodelingProceedings of the National Academy of Sciences of the United States of America, 2004