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Intracellular pH controls WNT downstream of glycolysis in amniote embryos

Author

Listed:
  • Masayuki Oginuma

    (Harvard Medical School
    Brigham and Women’s Hospital
    IMCR, Gunma University)

  • Yukiko Harima

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Oscar A. Tarazona

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Margarete Diaz-Cuadros

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Arthur Michaut

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Tohru Ishitani

    (IMCR, Gunma University
    RIMD, Osaka University)

  • Fengzhu Xiong

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Olivier Pourquié

    (Harvard Medical School
    Brigham and Women’s Hospital
    Harvard University)

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.

Suggested Citation

  • Masayuki Oginuma & Yukiko Harima & Oscar A. Tarazona & Margarete Diaz-Cuadros & Arthur Michaut & Tohru Ishitani & Fengzhu Xiong & Olivier Pourquié, 2020. "Intracellular pH controls WNT downstream of glycolysis in amniote embryos," Nature, Nature, vol. 584(7819), pages 98-101, August.
  • Handle: RePEc:nat:nature:v:584:y:2020:i:7819:d:10.1038_s41586-020-2428-0
    DOI: 10.1038/s41586-020-2428-0
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    Cited by:

    1. Yi Liu & Efren Reyes & David Castillo-Azofeifa & Ophir D. Klein & Todd Nystul & Diane L. Barber, 2023. "Intracellular pH dynamics regulates intestinal stem cell lineage specification," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Haipeng Fu & Tingyu Wang & Xiaohui Kong & Kun Yan & Yang Yang & Jingyi Cao & Yafei Yuan & Nan Wang & Kehkooi Kee & Zhi John Lu & Qiaoran Xi, 2022. "A Nodal enhanced micropeptide NEMEP regulates glucose uptake during mesendoderm differentiation of embryonic stem cells," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Fjodor Merkuri & Megan Rothstein & Marcos Simoes-Costa, 2024. "Histone lactylation couples cellular metabolism with developmental gene regulatory networks," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Marina Sanaki-Matsumiya & Mitsuhiro Matsuda & Nicola Gritti & Fumio Nakaki & James Sharpe & Vikas Trivedi & Miki Ebisuya, 2022. "Periodic formation of epithelial somites from human pluripotent stem cells," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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