PUBLICATION
Manic Fringe promotes endothelial-to-mesenchymal transition mediated by the Notch signalling pathway during heart valve development
- Authors
- Yang, J., Wang, Z., Zhou, Y., Jiang, S., Qin, X., Xu, Z., Wang, Y., Zuo, M., Meng, Z., Chen, S., Wang, Q., Wang, J., Sun, K.
- ID
- ZDB-PUB-241114-27
- Date
- 2024
- Source
- Journal of molecular medicine (Berlin, Germany) 103(1): 51-71 (Journal)
- Registered Authors
- Keywords
- Antisense morpholino oligonucleotides, Endothelial mesenchymal transition, Heart valve development, Manic Fringe, Notch signalling pathway, Whole-exome sequencing
- MeSH Terms
-
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Endothelial Cells/metabolism
- Receptors, Notch*/genetics
- Receptors, Notch*/metabolism
- Glycosyltransferases/genetics
- Glycosyltransferases/metabolism
- Mutation
- Humans
- Heart Valves*/embryology
- Heart Valves*/metabolism
- Heart Valves*/pathology
- Signal Transduction*
- Gene Expression Regulation, Developmental
- Animals
- Zebrafish*
- Mice
- Epithelial-Mesenchymal Transition*/genetics
- PubMed
- 39528804 Full text @ J. Mol. Med.
Citation
Yang, J., Wang, Z., Zhou, Y., Jiang, S., Qin, X., Xu, Z., Wang, Y., Zuo, M., Meng, Z., Chen, S., Wang, Q., Wang, J., Sun, K. (2024) Manic Fringe promotes endothelial-to-mesenchymal transition mediated by the Notch signalling pathway during heart valve development. Journal of molecular medicine (Berlin, Germany). 103(1):51-71.
Abstract
A fundamental event in the formation of heart valves involves the transformation of endocardial cells within the outflow tract (OFT) and atrioventricular canal (AVC) cushions through a process known as endothelial-to-mesenchymal transition (EndMT). Aberrant EndMT is a primary cause of congenital valvular malformations. Manic Fringe (MFNG) has been previously associated with cardiovascular development, although its role in heart valve development remains underexplored. In this study, we seek to enhance our understanding of MFNG's involvement in valve formation and its association with EndMT. Staining results of histological section revealed the expression of MFNG in the AVC and OFT from embryonic day 9.5 to 10.5 (E9.5-E10.5), when EndMT takes place. Cellular data demonstrated that MFNG exerts a positive regulatory influence on the EndMT process, promoting endothelial cell (EC) migration by enhancing the activity of the Notch signalling pathway. MFNG knockdown mediated by antisense morpholino oligonucleotides (MO) injection caused abnormal development of the heart and valves in zebrafish. Furthermore, through whole-exome sequencing (WES), we identified a heterozygous MFNG mutation in patients diagnosed with tetralogy of Fallot-pulmonary valve stenosis (TOF-PS). Cellular and molecular assays confirmed that this deleterious mutation reduced MFNG expression and hindered the EndMT process. In summary, our study verifies that MFNG plays a role in promoting EndMT mediated by the Notch signalling pathway during the heart and valve development. The MFNG deleterious variant induces MFNG loss of function, potentially elucidating the underlying molecular mechanisms of MFNG's involvement in the pathogenesis of congenital heart valve defects. These observations contribute to our current genetic understanding of congenital heart valve disease and may provide a potential target for prenatal diagnosis and treatment. KEY MESSAGES: Our examination revealed, for the first time, that MFNG exhibited high expression levels during EndMT of heart valve development in mice. Our findings provide compelling evidence that MFNG plays a role in promoting EndMT mediated by the Notch signalling pathway. Our results identified, for the first time, a deleterious MFNG p. T77M variant that inhibited the EndMT process by downregulating the activity of the Notch signalling pathway, thereby preventing the normal valve formation. MFNG may serve as an early diagnostic marker and an effective therapeutic target for the clinical treatment of congenital heart valve defects.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping