期刊
NATURE CELL BIOLOGY
卷 22, 期 4, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41556-020-0483-2
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资金
- INSERM/CNRS, Atip-avenir, Plan cancer, La ligue contre le cancer nationale et regionale
- INCa
- Fondation ARC
- Centre Leon Berard
- Fondation pour la recherche medicale
- National Institutes of Health [R01-HD081534]
- ANR
- ERC
- DFG Forschergruppe 2722
- Max Planck Society
Netrin-1, via precise Neo1/Unc5B stoichiometry, promotes naive pluripotency, embryonic stem cell self-renewal in combination with leukaemia inhibitory factor, and the formation of the mouse epiblast in vivo. In mouse embryonic stem cells (mESCs), chemical blockade of Gsk3 alpha/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 Gsk3 alpha/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 Gsk3 alpha/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.
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