Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E-cadherin

Abstract

Epicardial epithelial-mesenchymal transition (EMT) is hypothesized to generate cardiovascular progenitor cells that differentiate into various cell types, including coronary smooth muscle and endothelial cells, perivascular and cardiac interstitial fibroblasts and cardiomyocytes. Here we show that an epicardial-specific knockout of Wt1 leads to a reduction of mesenchymal progenitor cells and their derivatives. We demonstrate that Wt1 is essential for repression of the epithelial phenotype in epicardial cells and during Embryonic Stem (ES) cell differentiation, through direct transcriptional regulation of Snail (Snai1) and E-cadherin (Cdh1), two of the major mediators of EMT. Some mesodermal lineages fail to form in Wt1 null embryoid bodies but this effect is rescued by the expression of Snai1, underlining the importance of EMT in generating these differentiated cells. These new insights into the molecular mechanisms regulating cardiovascular progenitor cells and EMT will shed light on the pathogenesis of heart diseases and may help the development of cell based therapies.

The Wilms’ tumour suppressor Wt1 is a major regulator of tumour angiogenesis and progression

“…To determine a functional relevance of Wt1 for tumour vessel formation and tumorigenesis, we used Wt1 conditional knockout mice (Wt1 lox/lox ) 17 crossed either with a tamoxifen-inducible Tie2-Cre 18 or VE-cadherin-Cre 19 (Supplementary Table 1). Both of them have been described to be active in endothelial cells.…”

Expression of Id2 in the second heart field and cardiac defects in Id2 knock‐out mice

“…Wilms Tumor-1 (WT-1) is expressed during development in the pro-epicardial organ, the epicardium, and the epicardial-derived cells (EPDCs) (Mahtab et al, 2008), and has a function in epicardial epithelial-mesenchymal transformation (EMT) necessary for cardiovascular progenitor cell formation (Martinez-Estrada et al, 2010). The hyperpolarization-activated cyclic nucleotide gated channel 4 (HCN4) has a role in generation of the so-called ''funny'' current I(f), important for pacemaker activity (automaticity) in the SAN.…”

Functional Role of WT1 in Prostate Cancer

“…WT1 expression accompanies the opposite developmental role, epithelial to mesenchymal transition (EMT), in the developing heart where epithelial cells transform into motile mesenchymal cells that contribute to the organ's cellular structure and generate important signals (27). Furthermore, it has been demonstrated that WT1 is required for cardiovascular progenitor cell formation through the upregulation of Snail and downregulation of E-cadherin, two of the major molecules involved in EMT (28). Although WT1 has been proposed to regulate EMT by repressing E-cadherin; more recently, WT1 has been linked to the regulation of epicardial EMT through the β-catenin and retinoic acid signaling pathways (29).…”

“…Initial studies in NIH-3T3 cells, in which it was demonstrated that E-cadherin is a WT1 target gene (62), and studies in cardiac epithelial cells have established the role of WT1 in E-cadherin regulation (28). E-cadherin is a transmembrane protein that mediates epithelial cell-cell interactions in the adherent junctions of the plasma membrane (63) through homophilic proteinprotein interactions (64).…”

“…While initial experiments associated growth suppression and characteristics of epithelial differentiation, including upregulation of E-cadherin, with stable expression of WT1 in NIH 3T3 cells (62), more recent studies in cardiac epithelial cells showed that WT1 transcriptionally repressed E-cadherin expression both directly and indirectly by the upregulation of Snail (28). Furthermore, it has been demonstrated that WT1 expression promotes metastasis and invasion in nonsmall-cell lung carcinoma patients through the suppression of E-cadherin (90).…”