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First published online 11 March 2009
doi: 10.1242/dev.033951

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Activin/Nodal signalling maintains pluripotency by controlling Nanog expression

Ludovic Vallier^1,*, Sasha Mendjan¹, Stephanie Brown¹, Zhenzhi Chng¹, Adrian Teo¹, Lucy E. Smithers^2,, Matthew W. B. Trotter^1,2, Candy H.-H. Cho¹, Amelie Martinez³, Peter Rugg-Gunn^1,, Gabrielle Brons¹ and Roger A. Pedersen¹

¹ Department of Surgery and Laboratory For Regenerative Medicine, West Forvie Building, Robinson Way, University of Cambridge, Cambridge CB2 0SZ, UK.
² CR-UK Viral Oncology Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.
³ Laboratoire de transfert de gènes dans le foie: applications thérapeutiques. Inserm U804, Université Paris XI, 94276 Le Kremlin Bicêtre, France.

^* Author for correspondence (e-mail: lv225{at}cam.ac.uk)

Accepted 16 February 2009

The pluripotent status of embryonic stem cells (ESCs) confers upon them the capacity to differentiate into the three primary germ layers, ectoderm, mesoderm and endoderm, from which all the cells of the adult body are derived. An understanding of the mechanisms controlling pluripotency is thus essential for driving the differentiation of human pluripotent cells into cell types useful for clinical applications. The Activin/Nodal signalling pathway is necessary to maintain pluripotency in human ESCs and in mouse epiblast stem cells (EpiSCs), but the molecular mechanisms by which it achieves this effect remain obscure. Here, we demonstrate that Activin/Nodal signalling controls expression of the key pluripotency factor Nanog in human ESCs and in mouse EpiSCs. Nanog in turn prevents neuroectoderm differentiation induced by FGF signalling and limits the transcriptional activity of the Smad2/3 cascade, blocking progression along the endoderm lineage. This negative-feedback loop imposes stasis in neuroectoderm and mesendoderm differentiation, thereby maintaining the pluripotent status of human ESCs and mouse EpiSCs.

Key words: Nanog, hESCs, Activin, Nodal, Smad2/3, Neuroectoderm, Endoderm, Mesendoderm, Extraembryonic, Mouse, Human

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Activin and Nanog: a pluripotent mix

Development 2009 136: e803. [Full Text]  

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