Formation of the body of vertebrate embryos proceeds sequentially by posterior addition of tissues from the tail bud. Cells of the tail bud and the posterior presomitic mesoderm, which control posterior elongation 1 , exhibit a high level of aerobic glycolysis that is reminiscent of the metabolic status of cancer cells experiencing the Warburg effect 2 , 3 . Glycolytic activity downstream of fibroblast growth factor controls WNT signalling in the tail bud 3 . In the neuromesodermal precursors of the tail bud 4 , WNT signalling promotes the mesodermal fate that is required for sustained axial elongation, at the expense of the neural fate 3 , 5 . How glycolysis regulates WNT signalling 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 cells to show that these cells exhibit an inverted pH gradient, with the extracellular pH lower than the intracellular pH, as observed in cancer cells 6 . Our data suggest that glycolysis increases extrusion of lactate coupled to protons via the monocarboxylate symporters. This contributes to elevating the intracellular pH in these cells, which creates a favourable chemical environment for non-enzymatic β-catenin acetylation downstream of WNT signalling. 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 tumour cells reactivate a developmental metabolic programme. The authors show that metabolic activity leads to an increase in the intracellular pH of neuromesodermal precursors, and that this increase in pH, by allowing post-translational modification of β-catenin, is required for the activation of WNT signalling and mesodermal fate acquisition.

中文翻译：

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细胞内 pH 控制羊膜胚胎糖酵解的 WNT 下游


脊椎动物胚胎体的形成是通过尾芽的后部添加组织顺序进行的。控制后伸长 1 的尾芽和后前体中胚层的细胞表现出高水平的有氧糖酵解，这让人想起经历 Warburg 效应的癌细胞的代谢状态 2 , 3 。成纤维细胞生长因子下游的糖酵解活性控制尾芽中的 WNT 信号传导 3 。在尾芽的神经中胚层前体中 4 ，WNT 信号传导促进持续轴向伸长所需的中胚层命运，但以牺牲神经命运为代价 3, 5 。糖酵解如何调节尾芽中的 WNT 信号传导目前尚不清楚。在这里，我们使用诱导多能干细胞在体外分化的鸡胚胎和人尾芽样细胞来证明这些细胞表现出倒置的 pH 梯度，细胞外 pH 值低于细胞内 pH，正如在癌细胞中观察到的 6 。我们的数据表明，糖酵解增加了通过单羧酸同向转运蛋白与质子偶联的乳酸的挤出。这有助于提高这些细胞的胞内 pH 值，从而为 WNT 信号下游的非酶促 β-连环蛋白乙酰化创造有利的化学环境。由于乙酰化 β-连环蛋白促进中胚层而不是神经命运 7 ，这最终导致中胚层转录 WNT 靶标的激活和尾芽前体中轴旁中胚层的规范。我们的工作支持一些肿瘤细胞重新激活发育代谢程序的观点。 作者表明，代谢活动会导致神经中胚层前体的细胞内 pH 值升高，而这种 pH 值的升高（通过允许 β-连环蛋白的翻译后修饰）是激活 WNT 信号传导和中胚层命运获得所必需的。