Sempou, EmilyKostiuk, ValentynaZhu, JieCecilia Guerra, M.Tyan, LeonidHwang, WoongCamacho-Aguilar, ElenaCaplan, Michael J.Zenisek, DavidWarmflash, AryehOwens, Nick D. L.Khokha, Mustafa K.2022-12-132022-12-132022Sempou, Emily, Kostiuk, Valentyna, Zhu, Jie, et al.. "Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR." <i>Nature Communications,</i> 13, (2022) Springer Nature: https://doi.org/10.1038/s41467-022-34363-w.https://hdl.handle.net/1911/114119Transitioning from pluripotency to differentiated cell fates is fundamental to both embryonic development and adult tissue homeostasis. Improving our understanding of this transition would facilitate our ability to manipulate pluripotent cells into tissues for therapeutic use. Here, we show that membrane voltage (Vm) regulates the exit from pluripotency and the onset of germ layer differentiation in the embryo, a process that affects both gastrulation and left-right patterning. By examining candidate genes of congenital heart disease and heterotaxy, we identify KCNH6, a member of the ether-a-go-go class of potassium channels that hyperpolarizes the Vm and thus limits the activation of voltage gated calcium channels, lowering intracellular calcium. In pluripotent embryonic cells, depletion of kcnh6 leads to membrane depolarization, elevation of intracellular calcium levels, and the maintenance of a pluripotent state at the expense of differentiation into ectodermal and myogenic lineages. Using high-resolution temporal transcriptome analysis, we identify the gene regulatory networks downstream of membrane depolarization and calcium signaling and discover that inhibition of the mTOR pathway transitions the pluripotent cell to a differentiated fate. By manipulating Vm using a suite of tools, we establish a bioelectric pathway that regulates pluripotency in vertebrates, including human embryonic stem cells.engThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.Journal articles41467-022-34363-whttps://doi.org/10.1038/s41467-022-34363-w