Intracellular pH Controls WNT Downstream of Glycolysis in Amniote Embryos

Abstract

Formation of the body of vertebrate embryos proceeds sequentially by posterior addition of tissues from the tail bud. Cells of the tail bud and posterior Presomitic Mesoderm (PSM), which control posterior elongation (1), exhibit a high level of aerobic glycolysis which is reminiscent of the metabolic status of cancer cells experiencing Warburg effect (2, 3). Glycolytic activity downstream of FGF controls Wnt signaling in the tail bud (3). In the Neuro-Mesodermal precursors (NMP) of the tail bud (4), Wnt signaling promotes the mesodermal fate required for sustained axial elongation, at the expense of the neural fate (3, 5). How glycolysis regulates Wnt signaling in the tail bud is currently unknown. Here we used chicken embryos and human tail bud-like cells differentiated in vitro from induced Pluripotent Stem (iPS) cells to show that these cells exhibit an inverted pH gradient, with extracellular pH (pHe) lower than intracellular pH (pHi), as observed in cancer cells (6). Our data suggest that glycolysis increases extrusion of lactate coupled to protons via the monocarboxylate (MCT) symporters. This contributes to elevate the pHi in these cells, creating a favorable chemical environment for non-enzymatic β-catenin acetylation downstream of Wnt signaling. As acetylated β-catenin promotes mesodermal rather than neural fate (7), this ultimately leads to activation of mesodermal transcriptional Wnt targets and specification of the paraxial mesoderm in tail bud precursors. Our work supports the notion that some tumor cells reactivate a developmental metabolic program.