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

Huyghe, A., Furlan, G., Ozmadenci, D., Galonska, C., Charlton, J., Gaume, X., et al. (2020). Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling. Nature Cell Biology, 22(4), 389-400. doi:10.1038/s41556-020-0483-2.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-0A48-F Version Permalink: http://hdl.handle.net/21.11116/0000-0006-0A49-E
Genre: Journal Article

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 Creators:
Huyghe, Aurélia , Author
Furlan, Giacomo , Author
Ozmadenci, Duygu , Author
Galonska, Christina1, Author              
Charlton, Jocelyn1, Author              
Gaume, Xavier , Author
Combémorel, Noémie , Author
Riemenschneider, Christina1, Author              
Allègre, Nicolas , Author
Zhang, Jenny , Author
Wajda, Pauline , Author
Rama, Nicolas , Author
Vieugué, Pauline , Author
Durand, Isabelle , Author
Brevet , Marie , Author
Gadot, Nicolas , Author
Imhof, Thomas , Author
Merrill , Bradley J. , Author
Koch, Manuel, Author
Mehlen, Patrick , Author
Chazaud, Claire , AuthorMeissner, Alexander1, Author              Lavial , Fabrice , Author more..
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              

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 Abstract: 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.

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Language(s): eng - English
 Dates: 2020-03-302020-04
 Publication Status: Published in print
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/s41556-020-0483-2
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Title: Nature Cell Biology
  Other : 'Nat. Cell Biol.'
Source Genre: Journal
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Publ. Info: London : Springer Nature
Pages: 12 Volume / Issue: 22 (4) Sequence Number: - Start / End Page: 389 - 400 Identifier: ISSN: 1465-7392
CoNE: https://pure.mpg.de/cone/journals/resource/954925625310