Specific GATA Factors Act as Conserved Inducers of an Endodermal-EMT

Abstract

The epithelial-to-mesenchymal transition (EMT) converts cells from static epithelial to migratory mesenchymal states (Hay, 1995). Here, we demonstrate that EMT in the Drosophila endoderm is dependent on the GATA-factor Serpent (Srp), and that Srp acts as a potent trigger for this transition when activated ectopically. We show that Srp affects endodermal-EMT through a downregulation of junctional dE-Cadherin (dE-Cad) protein, without a block in its transcription. Moreover, the relocalization of dE-Cad is achieved through the direct repression of crumbs (crb) by Srp. Finally, we show that hGATA-6, an ortholog of Srp, induces a similar transition in mammalian cells. Similar to Srp, hGATA-6 acts through the downregulation of junctional E-Cad, without blocking its transcription, and induces the repression of a Crumbs ortholog, crb2. Together, these results identify a set of GATA factors as a conserved alternative trigger to repress epithelial characteristics and confer migratory capabilities on epithelial cells in development and pathogenesis.

Epithelial-mesenchymal transitions: insights from development

“…TGF receptors localized in tight junctions trigger non-canonical pathways, leading to RhoA ubiquitylation and degradation, and the destabilization of cortical actin microfilamentassociated tight junctions. The activation of transcriptional repressors, such as Snail and Serpent (Srp/GATA), downregulates genes encoding junctional proteins, including E-cadherin, claudins and occludin, thus compromising epithelial integrity (Spaderna et al, 2008;Whiteman et al, 2008;Campbell et al, 2011). EPB4.1L5 sequesters p120-catenin, which in turn weakens adherens junctions binding to paxillin and promotes 1-integrin-based cell-matrix adhesion.…”

“…1-Integrin signaling complex presumably contains FAK and Src. In Drosophila, partial EMT in the posterior midgut and is controlled by Srp (Campbell et al, 2011). Srp represses an apical polarity gene, Crb, resulting in the re-distribution of E-cadherin (not shown).…”

“…In Drosophila, the posterior midgut joins the anterior midgut in a partial EMT. During this process, Serpent, an ortholog of GATA repressor, represses Crumbs transcription (Campbell et al, 2011). In addition, signaling regulatory molecules act directly on polarity proteins, bypassing transcription factors, such as Snail and Zeb1.…”

At new heights – endodermal lineages in development and disease

“…Examining endoderm development in Drosophila, Kyra Campbell (Institut de Biologia Molecular de Barcelona-CSIC, Institut de Recerca Biomedica de Barcelona, Spain) described how transient expression of the Gata4/6 homolog serpent initiates epithelial-mesenchymal transition in the endoderm by downregulating Crumbs, resulting in a loss of apicobasal polarity and delocalization of E-Cadherin (Campbell et al, 2011). Dynamic E-Cadherin punctae are maintained throughout endoderm migration, and cell tracking shows that it is required for coordinating collective migration of midgut progenitors.…”

Drosophila primordial germ cell migration requires epithelial remodeling of the endoderm

“…Concomitant with PGC migration, the endoderm undergoes epithelial remodeling as part of an epithelial to mesenchymal transition (EMT) (Campbell et al, 2011;Campos-Ortega and Hartenstein, 1985). Discontinuities in circumferential adherens junctions and intercellular spaces between endodermal cells observed by electron microscopy have been postulated to act as exit sites for PGCs, although their functional role has never been tested (Callaini et al, 1995;Jaglarz and Howard, 1995).…”