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

Animals Cell Line Embryo, Mammalian Extracellular Signal-Regulated MAP Kinases / genetics Focal Adhesion Kinase 1 / genetics Gene Expression Regulation, Developmental Glycogen Synthase Kinase 3 beta / antagonists & inhibitors Humans Isoenzymes / antagonists & inhibitors Leukemia Inhibitory Factor / genetics MAP Kinase Kinase 1 / antagonists & inhibitors MAP Kinase Kinase 2 / antagonists & inhibitors Male Mice Mice, Knockout Mice, SCID Mouse Embryonic Stem Cells / cytology Nerve Tissue Proteins / genetics Netrin Receptors / genetics Netrin-1 / genetics Pluripotent Stem Cells / cytology Protein Phosphatase 2 / genetics Receptors, Cell Surface / genetics Wnt Signaling Pathway / genetics beta Catenin / genetics

Journal

Nature cell biology

ISSN: 1476-4679

Titre abrégé: Nat Cell Biol

Pays: England

ID NLM: 100890575

Informations de publication

Date de publication:
04 2020

Historique:

received: 03 11 2017

accepted: 13 02 2020

pubmed: 2 4 2020

medline: 21 4 2020

entrez: 2 4 2020

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41556-020-0483-2 PMID: 32231305

pubmed: 32231305

doi: 10.1038/s41556-020-0483-2

pii: 10.1038/s41556-020-0483-2

doi:

Substances chimiques

CTNNB1 protein, mouse 0

Isoenzymes 0

Leukemia Inhibitory Factor 0

Lif protein, mouse 0

NEO1 protein, human 0

Nerve Tissue Proteins 0

Netrin Receptors 0

Ntn1 protein, mouse 0

PPP2R2C protein, human 0

Receptors, Cell Surface 0

UNC5B protein, human 0

Unc5b protein, mouse 0

beta Catenin 0

Netrin-1 158651-98-0

Focal Adhesion Kinase 1 EC 2.7.10.2

Ptk2 protein, mouse EC 2.7.10.2

Glycogen Synthase Kinase 3 beta EC 2.7.11.1

Gsk3b protein, mouse EC 2.7.11.1

Extracellular Signal-Regulated MAP Kinases EC 2.7.11.24

MAP Kinase Kinase 1 EC 2.7.12.2

MAP Kinase Kinase 2 EC 2.7.12.2

Map2k1 protein, mouse EC 2.7.12.2

Map2k2 protein, mouse EC 2.7.12.2

Protein Phosphatase 2 EC 3.1.3.16

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

389-400

Subventions

Organisme : NICHD NIH HHS

ID : R01 HD081534

Pays : United States

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