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.

Citation

Aurélia Huyghe, Giacomo Furlan, Duygu Ozmadenci, Christina Galonska, Jocelyn Charlton, Xavier Gaume, Noémie Combémorel, Christina Riemenschneider, Nicolas Allègre, Jenny Zhang, Pauline Wajda, Nicolas Rama, Pauline Vieugué, Isabelle Durand, Marie Brevet, Nicolas Gadot, Thomas Imhof, Bradley J Merrill, Manuel Koch, Patrick Mehlen, Claire Chazaud, Alexander Meissner, Fabrice Lavial. Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling. Nature cell biology. 2020 Apr;22(4):389-400

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PMID: 32231305

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