Regulated changes in cell adhesion enable mesoderm cells to migrate away from the primitive streak during gastrulation. Fibroblast growth factor (Fgf) signalling is important for this process as it downregulates the expression of E-Cadherin, by inducing the E-Cadherin repressor Snail, to promote epithelial to mesenchymal transition (EMT). In a study published in Cell, Niswander and colleagues identify a p38 interacting protein (p38IP) which downregulates E-Cadherin in an Fgf- and Snail-independent manner, by activating p38 MAP kinase. These findings represent a novel mechanism for promoting EMT during gastrulation.

droopy eye (drey) mutant embryos exhibit a variety of phenotypes, including neural tube closure and gastrulation defects. The authors show that the drey mutation disrupts splicing of the D3Ertd300e:p38-interacting protein (p38IP) transcript, which is expressed ubiquitously during gastrulation. Both endogenous and exogenously expressed p38IP and p38 co-immunoprecipitate from 293T cells but more importantly, the phosphorylation of p38 and its substrates was reduced in p38IP mutant embryonic tissue, indicating that p38IP is required for p38 activation in vivo.

The mesoderm migration defects in mutant embryos homozygous for the more severe p38IP^RRK allele (null or severe hypomorph) are remarkably similar to those seen in Fgfr1 and Fgf8 mutants. However, unlike the Fgf mutants, the mesoderm is specified correctly and Snail is expressed at normal levels. Despite the fact that the levels of E-Cadherin transcript are downregulated in p38IP mutant embryos, E-Cadherin protein levels remain high at cell-cell junctions, hinting that p38IP functions to downregulate E-Cadherin at the protein rather than at the transcriptional level.

To shed some light on the mechanism through which p38IP affects mesoderm migration, the authors examined the migration of primitive streak explants on fibronectin-coated plates. They found that the migration defects of mutant mesoderm cells were rescued upon incubation with a function-perturbing E-Cadherin antibody, and that a p38 kinase inhibitor prevented the migration of wild type explants. These results suggest that decreased activation of p38 and impaired downregulation of the E-cadherin protein underlie the gastrulation defects of p38IP^RRK mutants.

In summary, this paper suggests that a non-redundant pathway, involving p38IP and p38 regulates E-Cadherin levels during gastrulation, independently of Fgf and Snail. The ability to downregulate E-Cadherin at both the transcriptional and protein level could help ensure a rapid, and thus timely, EMT.

Author: Monica Hoyos-Flight