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Mmp15 is a direct target of Snai1 during endothelial to mesenchymal transformation and endocardial cushion development.
- Source :
-
Developmental biology [Dev Biol] 2011 Nov 15; Vol. 359 (2), pp. 209-21. Date of Electronic Publication: 2011 Sep 05. - Publication Year :
- 2011
-
Abstract
- Cardiac valves originate from endocardial cushions (EC) formed by endothelial-to-mesenchymal transformation (EMT) during embryogenesis. The zinc-finger transcription factor Snai1 has previously been reported to be important for EMT during organogenesis, yet its role in early valve development has not been directly examined. In this study we show that Snai1 is highly expressed in endothelial, and newly transformed mesenchyme cells during EC development. Mice with targeted snai1 knockdown display hypocellular ECs at E10.5 associated with decreased expression of mesenchyme cell markers and downregulation of the matrix metalloproteinase (mmp) family member, mmp15. Snai1 overexpression studies in atrioventricular canal collagen I gel explants indicate that Snai1 is sufficient to promote mmp15 expression, cell transformation, and mesenchymal cell migration and invasion. However, treatment with the catalytically active form of MMP15 promotes cell motility, and not transformation. Further, we show that Snai1-mediated cell migration requires MMP activity, and caMMP15 treatment rescues attenuated migration defects observed in murine ECs following snai1 knockdown. Together, findings from this study reveal previously unappreciated mechanisms of Snai1 for the direct regulation of MMPs during EC development.<br /> (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Binding Sites genetics
COS Cells
Cell Movement drug effects
Cells, Cultured
Chick Embryo
Chlorocebus aethiops
Dipeptides pharmacology
Endocardial Cushions cytology
Endocardial Cushions embryology
Endothelium cytology
Endothelium embryology
Female
Gene Expression Regulation, Developmental
Heart Valves embryology
Heart Valves metabolism
Immunohistochemistry
Male
Matrix Metalloproteinase 15 genetics
Matrix Metalloproteinase Inhibitors
Mesoderm cytology
Mesoderm embryology
Mice
Mice, Knockout
Promoter Regions, Genetic genetics
Protease Inhibitors pharmacology
Protein Binding
Reverse Transcriptase Polymerase Chain Reaction
Snail Family Transcription Factors
Time Factors
Transcription Factors genetics
Endocardial Cushions metabolism
Endothelium metabolism
Matrix Metalloproteinase 15 metabolism
Mesoderm metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1095-564X
- Volume :
- 359
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Developmental biology
- Publication Type :
- Academic Journal
- Accession number :
- 21920357
- Full Text :
- https://doi.org/10.1016/j.ydbio.2011.08.022