Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling
- Huyghe, Aurélia
- Furlan, Giacomo
- Ozmadenci, Duygu
- Galonska, Christina
- Charlton, Jocelyn
- Gaume, Xavier
- Combémorel, Noémie
- Riemenschneider, Christina
- Allègre, Nicolas
- Zhang, Jenny
- Wajda, Pauline
- Rama, Nicolas
- Vieugué, Pauline
- Durand, Isabelle
- Brevet, Marie
- Gadot, Nicolas
- Imhof, Thomas
- Merrill, Bradley J
- Koch, Manuel
- Mehlen, Patrick
- Chazaud, Claire
- Meissner, Alexander
- Lavial, Fabrice
2020
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- Autor(en) / Beteiligte
- Huyghe, Aurélia
- Furlan, Giacomo
- Ozmadenci, Duygu
- Galonska, Christina
- Charlton, Jocelyn
- Gaume, Xavier
- Combémorel, Noémie
- Riemenschneider, Christina
- Allègre, Nicolas
- Zhang, Jenny
- Wajda, Pauline
- Rama, Nicolas
- Vieugué, Pauline
- Durand, Isabelle
- Brevet, Marie
- Gadot, Nicolas
- Imhof, Thomas
- Merrill, Bradley J
- Koch, Manuel
- Mehlen, Patrick
- Chazaud, Claire
- Meissner, Alexander
- Lavial, Fabrice
- Titel
- Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling
- Ist Teil von
- Nature cell biology, 2020-04, Vol.22 (4), p.389-400
- Ort / Verlag
- England
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1465-7392eISSN: 1476-4679DOI: 10.1038/s41556-020-0483-2Titel-ID: cdi_pubmed_primary_32231305
- Format
- –
- Schlagworte
- Animals, beta Catenin - genetics, beta Catenin - metabolism, Cell Line, Embryo, Mammalian, Extracellular Signal-Regulated MAP Kinases - genetics, Extracellular Signal-Regulated MAP Kinases - metabolism, Focal Adhesion Kinase 1 - genetics, Focal Adhesion Kinase 1 - metabolism, Gene Expression Regulation, Developmental, Glycogen Synthase Kinase 3 beta - antagonists & inhibitors, Glycogen Synthase Kinase 3 beta - genetics, Glycogen Synthase Kinase 3 beta - metabolism, Humans, Isoenzymes - antagonists & inhibitors, Isoenzymes - genetics, Isoenzymes - metabolism, Leukemia Inhibitory Factor - genetics, Leukemia Inhibitory Factor - metabolism, Male, MAP Kinase Kinase 1 - antagonists & inhibitors, MAP Kinase Kinase 1 - genetics, MAP Kinase Kinase 1 - metabolism, MAP Kinase Kinase 2 - antagonists & inhibitors, MAP Kinase Kinase 2 - genetics, MAP Kinase Kinase 2 - metabolism, Mice, Mice, Knockout, Mice, SCID, Mouse Embryonic Stem Cells - cytology, Mouse Embryonic Stem Cells - metabolism, Nerve Tissue Proteins - genetics, Nerve Tissue Proteins - metabolism, Netrin Receptors - genetics, Netrin Receptors - metabolism, Netrin-1 - genetics, Netrin-1 - metabolism, Pluripotent Stem Cells - cytology, Pluripotent Stem Cells - metabolism, Protein Phosphatase 2 - genetics, Protein Phosphatase 2 - metabolism, Receptors, Cell Surface - genetics, Receptors, Cell Surface - metabolism, Wnt Signaling Pathway - genetics