title: Mmp15 is a direct target of Snai1 during endothelial to mesenchymal transformation and endocardial cushion development.
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.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Florida 33101, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Tao
authors.forename: Agata K
authors.initials: AK
authors.lastname: Levay
authors.forename: Thomas
authors.initials: T
authors.lastname: Gridley
authors.forename: Joy
authors.initials: J
authors.lastname: Lincoln
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D004151:Dipeptides / Q000494:pharmacology; D054089:Endocardial Cushions / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D004727:Endothelium / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006351:Heart Valves / Q000196:embryology / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D053517:Matrix Metalloproteinase 15 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008648:Mesoderm / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D011480:Protease Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C507100:Mmp15 protein, mouse; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053517:Matrix Metalloproteinase 15