Here we show that the axon guidance cue Netrin-1 promotes naive pluripotency by triggering profound signalling, transcriptomic and epigenetic changes in mESCs. mouse embryonic stem cells (mESCs), chemical blockade of Gsk3α/β and Mek1/2 (2i) instructs a self-renewing ground state whose endogenous inducers are unknown.

13 Cellular Reprogramming and Oncogenesis Laboratory, Equipe labellisée la Ligue contre le cancer, Labex DEVweCAN, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon, France.

1 Cellular Reprogramming and Oncogenesis Laboratory, Equipe labellisée la Ligue contre le cancer, Labex DEVweCAN, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon, France.

12 Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France.

11 Institute for Dental Research and Oral Musculoskeletal Research, Center for Biochemistry, University of Cologne, Cologne, Germany.

10 Research Pathology platform, Department of translational research and innovation, Centre Léon Bérard, Lyon, France.9 Cytometry Facility, Université de Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, INSERM 1052, CNRS 5286, Lyon, France.8 Apoptosis, Cancer and Development Laboratory, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon, France.7 Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA.6 GReD, Université Clermont Auvergne, CNRS, INSERM, BP38, Clermont-Ferrand, France.5 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.4 Harvard Stem Cell Institute, Cambridge, MA, USA.3 Broad Institute of MIT and Harvard, Cambridge, MA, USA.

2 Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany.

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