| First Author | Huyghe A | Year | 2020 |
| Journal | Nat Cell Biol | Volume | 22 |
| Issue | 4 | Pages | 389-400 |
| PubMed ID | 32231305 | Mgi Jnum | J:291217 |
| Mgi Id | MGI:6443326 | Doi | 10.1038/s41556-020-0483-2 |
| Citation | Huyghe A, et al. (2020) Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling. Nat Cell Biol 22(4):389-400 |
| abstractText | In mouse embryonic stem cells (mESCs), chemical blockade of Gsk3alpha/beta 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 Gsk3alpha/beta 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 Gsk3alpha/beta and stabilize beta-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. |
