Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs.
Epithelial-mesenchymal transition (EMT) is required for mesodermal differentiation during development. The zinc-finger transcription factor, Snail1, can trigger EMT and is sufficient to transcriptionally reprogram epithelial cells toward a mesenchymal phenotype during neoplasia and fibrosis. 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 fibroblasts 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-deficient fibroblasts explanted atop the live chick chorioallantoic membrane lack tissue-invasive potential and fail to induce angiogenesis. These findings establish key functions for the EMT regulator Snail1 after terminal differentiation of mesenchymal cells.
Rowe
R Grant
RG
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Li
Xiao-Yan
XY
Hu
Yuexian
Y
Saunders
Thomas L
TL
Virtanen
Ismo
I
Garcia de Herreros
Antonio
A
Becker
Karl-Friedrich
KF
Ingvarsen
Signe
S
Engelholm
Lars H
LH
Bommer
Guido T
GT
Fearon
Eric R
ER
Weiss
Stephen J
SJ
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D020033:Protein Isoforms; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors