Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs

Abstract

Epithelial - mesenchymal transition (EMT) is required for mesodermal differentiation during development. The zinc-fi nger transcription factor, Snail1, can trigger EMT and is suffi cient to transcriptionally reprogram epithelial cells toward a mesenchymal phenotype during neoplasia and fi brosis. Whether Snail1 also regulates the behavior of terminally differentiated mesenchymal cells remains unexplored. Using a Snai1 conditional knockout model, we now identify Snail1 as a regulator of normal mesenchymal cell function. Snail1 expression in normal fi broblasts can be induced by agonists known to promote proliferation and invasion in vivo. When challenged within a tissue-like, three-dimensional extracellular matrix, Snail1-deficient fibroblasts exhibit global alterations in gene expression, which include defects in membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invasive activity. Snail1-defi cient fi broblasts explanted atop the live chick chorioallantoic membrane lack tissue-invasive potential and fail to induce angiogenesis. These fi ndings establish key functions for the EMT regulator Snail1 after terminal differentiation of mesenchymal cells. © 2009 Rowe et al.