Suppression of YAP safeguards human naïve pluripotency.
Human embryo
Pluripotency
Self-renewal
Stem cell
Trophectoderm
YAP
Journal
Development (Cambridge, England)
ISSN: 1477-9129
Titre abrégé: Development
Pays: England
ID NLM: 8701744
Informations de publication
Date de publication:
15 12 2022
15 12 2022
Historique:
received:
06
06
2022
accepted:
11
11
2022
pubmed:
19
11
2022
medline:
23
12
2022
entrez:
18
11
2022
Statut:
ppublish
Résumé
Propagation of human naïve pluripotent stem cells (nPSCs) relies on the inhibition of MEK/ERK signalling. However, MEK/ERK inhibition also promotes differentiation into trophectoderm (TE). Therefore, robust self-renewal requires suppression of TE fate. Tankyrase inhibition using XAV939 has been shown to stabilise human nPSCs and is implicated in TE suppression. Here, we dissect the mechanism of this effect. Tankyrase inhibition is known to block canonical Wnt/β-catenin signalling. However, we show that nPSCs depleted of β-catenin remain dependent on XAV939. Rather than inhibiting Wnt, we found that XAV939 prevents TE induction by reducing activation of YAP, a co-factor of TE-inducing TEAD transcription factors. Tankyrase inhibition stabilises angiomotin, which limits nuclear accumulation of YAP. Upon deletion of angiomotin-family members AMOT and AMOTL2, nuclear YAP increases and XAV939 fails to prevent TE induction. Expression of constitutively active YAP similarly precipitates TE differentiation. Conversely, nPSCs lacking YAP1 or its paralog TAZ (WWTR1) resist TE differentiation and self-renewal efficiently without XAV939. These findings explain the distinct requirement for tankyrase inhibition in human but not in mouse nPSCs and highlight the pivotal role of YAP activity in human naïve pluripotency and TE differentiation. This article has an associated 'The people behind the papers' interview.
Identifiants
pubmed: 36398796
pii: 283159
doi: 10.1242/dev.200988
pmc: PMC9845734
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
AMOTL2 protein, human
0
Angiomotins
0
beta Catenin
0
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
Tankyrases
EC 2.4.2.30
YAP-Signaling Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Medical Research Council
ID : MR/W025310/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1100526/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P00072X/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P00072X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1100526
Pays : United Kingdom
Informations de copyright
© 2022. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests G.G. and A.S. are inventors on a patent relating to human naïve pluripotent stem cells filed by the University of Cambridge, UK.
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