Mmp15 is a direct target of Snai1 during endothelial to mesenchymal transformation and endocardial cushion development. Dev Biol 2011 Nov 15;359(2):209-21
Date
09/17/2011Pubmed ID
21920357Pubmed Central ID
PMC3202673DOI
10.1016/j.ydbio.2011.08.022Scopus ID
2-s2.0-82455218930 (requires institutional sign-in at Scopus site) 44 CitationsAbstract
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.
Author List
Tao G, Levay AK, Gridley T, Lincoln JAuthor
Joy Lincoln PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBinding Sites
COS Cells
Cell Movement
Cells, Cultured
Chick Embryo
Dipeptides
Endocardial Cushions
Endothelium
Female
Gene Expression Regulation, Developmental
Heart Valves
Immunohistochemistry
Male
Matrix Metalloproteinase 15
Matrix Metalloproteinase Inhibitors
Mesoderm
Mice
Mice, Knockout
Promoter Regions, Genetic
Protease Inhibitors
Protein Binding
Reverse Transcriptase Polymerase Chain Reaction
Snail Family Transcription Factors
Time Factors
Transcription Factors