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Pubmed ID: 32231305
Publication Date: 2020/03/30

Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling.


In 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. Here we show that the axon guidance cue Netrin-1 promotes naive pluripotency by triggering profound signalling, transcriptomic and epigenetic changes in mESCs. Furthermore, we demonstrate that Netrin-1 can substitute for blockade of Gsk3α/β and Mek1/2 to sustain self-renewal of mESCs in combination with leukaemia inhibitory factor and regulates the formation of the mouse pluripotent blastocyst. Mechanistically, we reveal how Netrin-1 and the balance of its receptors Neo1 and Unc5B co-regulate Wnt and MAPK pathways in both mouse and human ESCs. Netrin-1 induces Fak kinase to inactivate Gsk3α/β and stabilize β-catenin while increasing the phosphatase activity of a Ppp2r2c-containing Pp2a complex to reduce Erk1/2 activity. Collectively, this work identifies Netrin-1 as a regulator of pluripotency and reveals that it mediates different effects in mESCs depending on its receptor dosage, opening perspectives for balancing self-renewal and lineage commitment.
Authors: Huyghe Aurélia , Furlan Giacomo , Ozmadenci Duygu , Galonska Christina , Charlton Jocelyn , Gaume Xavier , Combémorel Noémie , Riemenschneider Christina , Allègre Nicolas , Zhang Jenny , Wajda Pauline , Rama Nicolas , Vieugué Pauline , Durand Isabelle , Brevet Marie , Gadot Nicolas , Imhof Thomas , Merrill Bradley J , Koch Manuel , Mehlen Patrick , Chazaud Claire , Meissner Alexander , Lavial Fabrice ,

Reference:

  1. ncbi.nlm.nih.gov. [Last access 2020/03/30].

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