研究揭示羊膜胚胎細胞內pH調控WNT信號通路
作者：
小柯機器人發布時間：2020/6/28 10:40:23
美國哈佛醫學院Olivier Pourqui及其研究組的研究發現在羊膜胚胎，細胞內pH調控糖酵解下遊的WNT信號通路。該研究於2020年6月24日在線發表於國際學術期刊《自然》。
使用了雞胚和人誘導多能幹細胞體外分化的人尾芽樣細胞，研究人員發現這些細胞表現出反向的pH梯度，正如癌細胞中觀察到的那樣，細胞外pH低於細胞內pH。這些數據表明，糖酵解會增加乳酸質子的排放，這是通過單羧酸鹽共轉運體耦合實現的。這有助於提高這些細胞的細胞內pH，從而為WNT信號下遊的非酶促β-連環蛋白乙醯化創造了適宜的化學環境。
由於乙醯化的β-catenin促進中胚層而不是神經發育，這最終導致了中胚層WNT信號的轉錄激活和尾芽前體中近軸中胚層的特化。該工作支持了某些腫瘤細胞會重新激活發育代謝通路的觀點。
據介紹，脊椎動物胚體的形成是從尾芽到背組織添加依次進行的。尾芽和調控背部伸長的後早發性中胚層細胞表現出高度好氧的糖酵解，這與經歷了Warburg效應的癌細胞代謝狀態類似。成纖維細胞生長因子下遊的糖酵解活性影響尾芽組織WNT信號的傳導。在尾芽的神經中胚層前體中，WNT信號傳導以犧牲神經發育為代價促進了持續軸向伸長所需中胚層的發育。目前尚不清楚糖酵解如何調控尾芽中WNT信號的傳導。
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