Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance.
Fiche publication
Date publication
juillet 2015
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr PLATEROTI Michelina
Tous les auteurs :
Ozmadenci D, Féraud O, Markossian S, Kress E, Ducarouge B, Gibert B, Ge J, Durand I, Gadot N, Plateroti M, Bennaceur-Griscelli A, Scoazec JY, Gil J, Deng H, Bernet A, Mehlen P, Lavial F
Lien Pubmed
Résumé
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.
Mots clés
Animals, Cells, Cultured, Cellular Reprogramming, physiology, Fibroblasts, Gene Expression Regulation, physiology, Humans, Mice, Nerve Growth Factors, genetics, Netrin Receptors, Netrin-1, Pluripotent Stem Cells, physiology, Promoter Regions, Genetic, Receptors, Cell Surface, genetics, Recombinant Proteins, pharmacology, Signal Transduction, Tumor Suppressor Proteins, genetics
Référence
Nat Commun. 2015 Jul 8;6:7398