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Article Dans Une Revue Nature Cell Biology Année : 2020

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

Christina Galonska
  • Fonction : Auteur
Jocelyn Charlton
  • Fonction : Auteur
Noémie Combémorel
  • Fonction : Auteur
Christina Riemenschneider
  • Fonction : Auteur
Pauline Vieugué
  • Fonction : Auteur
Isabelle Durand
  • Fonction : Auteur
Marie Brevet
  • Fonction : Auteur
Thomas Imhof
  • Fonction : Auteur
Bradley Merrill
  • Fonction : Auteur
Patrick Mehlen
Manuel Koch
  • Fonction : Auteur
Claire Chazaud
  • Fonction : Auteur
Alexander Meissner
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-03102136 , version 1 (07-01-2021)

Identifiants

Citer

Aurélia Huyghe, Giacomo Furlan, Duygu Ozmadenci, Christina Galonska, Jocelyn Charlton, et al.. Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling. Nature Cell Biology, 2020, 22 (4), pp.389-400. ⟨10.1038/s41556-020-0483-2⟩. ⟨hal-03102136⟩
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