title: Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance.
abstract: The generation of induced pluripotent stem (iPS) cells holds great promise in regenerative medicine. The use of the transcription factors Oct4, Sox2, Klf4 and c-Myc for reprogramming is extensively documented, but comparatively little is known about soluble molecules promoting reprogramming. Here we identify the secreted cue Netrin-1 and its receptor DCC, described for their respective survival/death functions in normal and oncogenic contexts, as reprogramming modulators. In various somatic cells, we found that reprogramming is accompanied by a transient transcriptional repression of Netrin-1 mediated by an Mbd3/Mta1/Chd4-containing NuRD complex. Mechanistically, Netrin-1 imbalance induces apoptosis mediated by the receptor DCC in a p53-independent manner. Correction of the Netrin-1/DCC equilibrium constrains apoptosis and improves reprogramming efficiency. Our work also sheds light on Netrin-1's function in protecting embryonic stem cells from apoptosis mediated by its receptor UNC5b, and shows that the treatment with recombinant Netrin-1 improves the generation of mouse and human iPS cells.
authors.affiliation: Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Duygu
authors.initials: D
authors.lastname: Ozmadenci
authors.affiliation: INSERM U935, ESTeam Paris-Sud, Université Paris-Sud, Villejuif, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Féraud
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique, École Normale Supérieure de Lyon, 69364 Lyon, France.
authors.forename: Suzy
authors.initials: S
authors.lastname: Markossian
authors.affiliation: CGϕMC UMR 5534 - Université Lyon 1, Campus de la Doua, Bâtiment Gregor Mendel 16, Rue Dubois, 69622 Villeurbanne, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Kress
authors.affiliation: Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Ducarouge
authors.affiliation: Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gibert
authors.affiliation: Center for Life Sciences, Peking University, Yiheyuan Road Haidian District, Beijing 100871, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ge
authors.affiliation: Cytometry Facility, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Durand
authors.affiliation: Anipath, Université de Lyon, Hospices Civils de Lyon, Hôpital Edouard Herriot, Anatomie Pathologique, 69437 Lyon, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gadot
authors.affiliation: CGϕMC UMR 5534 - Université Lyon 1, Campus de la Doua, Bâtiment Gregor Mendel 16, Rue Dubois, 69622 Villeurbanne, France.
authors.forename: Michela
authors.initials: M
authors.lastname: Plateroti
authors.affiliation: INSERM U935, ESTeam Paris-Sud, Université Paris-Sud, Villejuif, France.
authors.forename: Annelise
authors.initials: A
authors.lastname: Bennaceur-Griscelli
authors.affiliation: Anipath, Université de Lyon, Hospices Civils de Lyon, Hôpital Edouard Herriot, Anatomie Pathologique, 69437 Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, W12 0NN, London, UK.
authors.forename: Jesus
authors.initials: J
authors.lastname: Gil
authors.affiliation: Center for Life Sciences, Peking University, Yiheyuan Road Haidian District, Beijing 100871, P.R. China.
authors.forename: Hongkui
authors.initials: H
authors.lastname: Deng
authors.affiliation: Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Agnes
authors.initials: A
authors.lastname: Bernet
authors.affiliation: Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
authors.affiliation: 1] Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France [2] Cellular Reprogramming and Oncogenesis Laboratory, ATIP/Avenir Laboratory, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Lavial
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000502:physiology*; D005347:Fibroblasts; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D000075386:Netrin Receptors; D000075388:Netrin-1; D039904:Pluripotent Stem Cells / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1