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MEKK3 initiates transforming growth factor beta 2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis.
- Source :
-
Circulation research [Circ Res] 2008 Dec 05; Vol. 103 (12), pp. 1430-40. Date of Electronic Publication: 2008 Nov 13. - Publication Year :
- 2008
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Abstract
- Congenital heart defects occur at a rate of 5% and are the most prevalent birth defects. A better understanding of the complex signaling networks regulating heart development is necessary to improve repair strategies for congenital heart defects. The mitogen-activated protein 3 kinase (MEKK3) is important to early embryogenesis, but developmental processes affected by MEKK3 during heart morphogenesis have not been fully examined. We identify MEKK3 as a critical signaling molecule during endocardial cushion development. We report the detection of MEKK3 transcripts to embryonic hearts before, during, and after cardiac cushion cells have executed epithelial-to-mesenchymal transition (EMT). MEKK3 is observed to endocardial cells of the cardiac cushions with a diminishing gradient of expression into the cushions. These observations suggest that MEKK3 may function during production of cushion mesenchyme as required for valvular development and septation of the heart. We used a kinase inactive form of MEKK3 (MEKK3(KI)) in an in vitro assay that recapitulates in vivo EMT and show that MEKK3(KI) attenuates mesenchyme formation. Conversely, constitutively active MEKK3 (ca-MEKK3) triggers mesenchyme production in ventricular endocardium, a tissue that does not normally undergo EMT. MEKK3-driven mesenchyme production is further substantiated by increased expression of EMT-relevant genes, including TGFbeta(2), Has2, and periostin. Furthermore, we show that MEKK3 stimulates EMT via a TGFbeta(2)-dependent mechanism. Thus, the activity of MEKK3 is sufficient for developmental EMT in the heart. This knowledge provides a basis to understand how MEKK3 integrates signaling cascades activating endocardial cushion EMT.
- Subjects :
- Animals
Cell Differentiation physiology
Endocardial Cushions cytology
Endocardial Cushions metabolism
Epithelial Cells metabolism
Gene Expression Regulation, Enzymologic physiology
MAP Kinase Kinase Kinase 3 deficiency
MAP Kinase Kinase Kinase 3 genetics
MAP Kinase Kinase Kinase 3 metabolism
Mesoderm cytology
Mesoderm metabolism
Mice
Endocardial Cushions embryology
Endocardial Cushions enzymology
Epithelial Cells cytology
Epithelial Cells enzymology
MAP Kinase Kinase Kinase 3 physiology
Mesoderm embryology
Morphogenesis physiology
Transforming Growth Factor beta2 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 103
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 19008476
- Full Text :
- https://doi.org/10.1161/CIRCRESAHA.108.180752