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

Christina K. Speirs, Kristin K. Jernigan, Seok Hyung Kim, Yong I. Cha, Fang Lin, Diane S. Sepich, Raymond N. DuBois, Ethan Lee, Lilianna Solnica-Krezel

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1327-1337
Number of pages11
JournalDevelopment
Volume137
Issue number8
DOIs
StatePublished - Apr 15 2010

Keywords

  • Cell adhesion
  • Gastrulation
  • Gβγ
  • Prostaglandin E
  • Snail
  • Zebrafish

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