Prostaglandin Gβγ signaling stimulates gastrulation movements by limiting cell adhesion through Snai1a stabilization

Gastrulation movements form the germ layers and shape them into the vertebrate body. Gastrulation entails a variety of cell behaviors, including directed cell migration and cell delamination, which are also involved in other physiological and pathological processes, such as cancer metastasis. Decreased Prostaglandin E₂ (PGE₂) synthesis due to interference with the Cyclooxygenase (Cox) and Prostaglandin E synthase (Ptges) enzymes halts gastrulation and limits cancer cell invasiveness, but how PGE₂ regulates cell motility remains unclear. Here we show that PGE ₂-deficient zebrafish embryos, impaired in the epiboly, internalization, convergence and extension gastrulation movements, exhibit markedly increased cell-cell adhesion, which contributes to defective cell movements in the gastrula. Our analyses reveal that PGE₂ promotes cell protrusive activity and limits cell adhesion by modulating E-cadherin transcript and protein, in part through stabilization of the Snai1a (also known as Snail1) transcriptional repressor, an evolutionarily conserved regulator of cell delamination and directed migration. We delineate a pathway whereby PGE₂ potentiates interaction between the receptor-coupled G protein βγ subunits and Gsk3β to inhibit proteasomal degradation of Snai1a. However, overexpression of β-catenin cannot stabilize Snai1a in PGE₂-deficient gastrulae. Thus, the Gsk3β-mediated and β-catenin-independent inhibition of cell adhesion by Prostaglandins provides an additional mechanism for the functional interactions between the PGE₂ and Wnt signaling pathways during development and disease. We propose that ubiquitously expressed PGE₂ synthesizing enzymes, by promoting the stability of Snai1a, enable the precise and rapid regulation of cell adhesion that is required for the dynamic cell behaviors that drive various gastrulation movements.