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美国哈佛医学院Olivier Pourqui及其研究组的研究发现在羊膜胚胎，细胞内pH调控糖酵解下游的WNT信号通路。该研究于2020年6月24日在线发表于国际学术期刊《自然》。

使用了鸡胚和人诱导多能干细胞体外分化的人尾芽样细胞，研究人员发现这些细胞表现出反向的pH梯度，正如癌细胞中观察到的那样，细胞外pH低于细胞内pH。这些数据表明，糖酵解会增加乳酸质子的排放，这是通过单羧酸盐共转运体耦合实现的。这有助于提高这些细胞的细胞内pH，从而为WNT信号下游的非酶促β-连环蛋白乙酰化创造了适宜的化学环境。

由于乙酰化的β-catenin促进中胚层而不是神经发育，这最终导致了中胚层WNT信号的转录激活和尾芽前体中近轴中胚层的特化。该工作支持了某些肿瘤细胞会重新激活发育代谢通路的观点。

据介绍，脊椎动物胚体的形成是从尾芽到背组织添加依次进行的。尾芽和调控背部伸长的后早发性中胚层细胞表现出高度好氧的糖酵解，这与经历了Warburg效应的癌细胞代谢状态类似。成纤维细胞生长因子下游的糖酵解活性影响尾芽组织WNT信号的传导。在尾芽的神经中胚层前体中，WNT信号传导以牺牲神经发育为代价促进了持续轴向伸长所需中胚层的发育。目前尚不清楚糖酵解如何调控尾芽中WNT信号的传导。

附：英文原文

Title: Intracellular pH controls WNT downstream of glycolysis in amniote embryos

Author: Masayuki Oginuma, Yukiko Harima, Oscar A. Tarazona, Margarete Diaz-Cuadros, Arthur Michaut, Tohru Ishitani, Fengzhu Xiong, Olivier Pourqui

Issue&Volume: 2020-06-24

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 the posterior presomitic mesoderm, which control posterior elongation1, exhibit a high level of aerobic glycolysis that is reminiscent of the metabolic status of cancer cells experiencing the Warburg effect2,3. Glycolytic activity downstream of fibroblast growth factor controls WNT signalling in the tail bud3. In the neuromesodermal precursors of the tail bud4, WNT signalling promotes the mesodermal fate that is required for sustained axial elongation, at the expense of the neural fate3,5. 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 cells6. 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 fate7, 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.

DOI: 10.1038/s41586-020-2428-0

Source: https://www.nature.com/articles/s41586-020-2428-0

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