Huyghe, Aurelia, Furlan, Giacomo, Ozmadenci, Duygu, Galonska, Christina, Charlton, Jocelyn, Gaume, Xavier, Combemorel, Noemie, Riemenschneider, Christina, Allegre, Nicolas, Zhang, Jenny, Wajda, Pauline, Rama, Nicolas, Vieugue, Pauline, Durand, Isabelle, Brevet, Marie, Gadot, Nicolas, Imhof, Thomas, Merrill, Bradley J., Koch, Manuel, Mehlen, Patrick, Chazaud, Claire, Meissner, Alexander and Lavial, Fabrice ORCID: 0000-0001-9752-4393 (2020). Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling. Nat. Cell Biol., 22 (4). LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4679

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Huyghe, AureliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Furlan, GiacomoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozmadenci, DuyguUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galonska, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Charlton, JocelynUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gaume, XavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Combemorel, NoemieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riemenschneider, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allegre, NicolasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wajda, PaulineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rama, NicolasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vieugue, PaulineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Durand, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brevet, MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gadot, NicolasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Imhof, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merrill, Bradley J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koch, ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mehlen, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chazaud, ClaireUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meissner, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lavial, FabriceUNSPECIFIEDorcid.org/0000-0001-9752-4393UNSPECIFIED
URN: urn:nbn:de:hbz:38-340101
DOI: 10.1038/s41556-020-0483-2
Journal or Publication Title: Nat. Cell Biol.
Volume: 22
Number: 4
Date: 2020
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-4679
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
EMBRYONIC STEM-CELLS; FOCAL ADHESION KINASE; GROUND-STATE; AXON OUTGROWTH; SELF-RENEWAL; PROTEINS; INHIBITION; CULTURE; FAMILY; DIFFERENTIATIONMultiple languages
Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34010

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