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Nat Commun 2022 Nov 05;131:6681. doi: 10.1038/s41467-022-34363-w.
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Membrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR.

Sempou E , Kostiuk V , Zhu J , Cecilia Guerra M , Tyan L , Hwang W , Camacho-Aguilar E , Caplan MJ , Zenisek D , Warmflash A , Owens NDL , Khokha MK .

Transitioning 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.

PubMed ID: 36335122
PMC ID: PMC9637099
Article link: Nat Commun
Grant support: [+]

Species referenced: Xenopus tropicalis
Genes referenced: atf1 atg13 bmp4 cacna1g cdx2 creb1 crem dand5 dppa2 eomes ets1 foxh1 foxi1 foxi4.2 foxj1 foxj1.2 foxl1 gsc isl1 kcnh1 kcnh6 krt12.4 lefty mespb mix1 mixer mtor myf5 myod1 nodal3.1 pam pitx2 pou5f3 pou5f3.2 pou5f3.3 rictor smad4 sox17b.1 sox2 sox3 sst.1 tbxt trim33 vegt ventx1 ventx1.2 ventx2.2
GO keywords: ubiquitin-protein transferase activity [+]
Antibodies: Tuba4b Ab5
Morpholinos: kcnh6 MO1
gRNAs referenced: cacna1c gRNA1 cacna1g gRNA1 kcnh6 gRNA1 kcnh6 gRNA2

Phenotypes: Xtr Wt + Hsa.KCNH6 mRNA [+]

Article Images: [+] show captions
References [+] :
Adams, Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates. 2006, Pubmed, Xenbase