Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling.
Nat Cell Biol
; 22(4): 389-400, 2020 04.
Article
en En
| MEDLINE
| ID: mdl-32231305
ABSTRACT
In mouse embryonic stem cells (mESCs), chemical blockade of Gsk3α/ß 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/ß 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/ß and stabilize ß-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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Receptores de Superficie Celular
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Regulación del Desarrollo de la Expresión Génica
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Vía de Señalización Wnt
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Netrina-1
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Receptores de Netrina
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Proteínas del Tejido Nervioso
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Nat Cell Biol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Francia