Mmp15 is a direct target of Snail during endothelial to mesenchymal transformation and endocardial cushion development

Cardiac valves originate from endocardial cushions (EC) formed by endothelial-to-mesenchymal transformation (EMT) during embryogenesis. The zinc-finger transcription factor Snail 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 Snail is highly expressed in endothelial, and newly transformed mesenchyme cells during EC development. Mice with targeted snail 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. Snail overexpression studies in atrioventricular canal collagen I gel explants indicate that Snail 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 Snail-mediated cell migration requires MMP activity, and caMMP15 treatment rescues attenuated migration defects observed in murine ECs following snail knockdown. Together, findings from this study reveal previously unappreciated mechanisms of Snail for the direct regulation of MMPs during EC development. (C) 2011 Elsevier Inc. All rights reserved.