Suppression of YAP safeguards human naïve pluripotency.
Suppression of YAP safeguards human naïve pluripotency.
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DOI：
10.1242/dev.200988
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发表时间：
2022-12-15
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
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人单纯多能干细胞(NPSCs)的增殖依赖于MEK/ERK信号通路的抑制。然而，抑制MEK/ERK也促进分化为滋养外胚层(TE)。因此，强大的自我更新需要压制命运。使用XAV939抑制tankyrase已被证明可以稳定人的nPSCs，并与TE抑制有关。在这里，我们剖析了这种效应的机制。已知Tankyrase抑制能阻断典型的Wnt/β-catenin信号转导。然而，我们发现缺失β-连环蛋白的nPSCs仍然依赖于XAV939。我们发现，XAV939不是抑制Wnt，而是通过减少TE诱导TEAD转录因子的辅助因子YAP的激活来阻止TE诱导。Tankyrase抑制可以稳定血管生成素，从而限制YAP的核积累。当Angiomotin家族成员AMOT和AMOTL2缺失时，核YAP增加，XAV939不能阻止TE的诱导。结构性活性YAP的表达类似地促进TE的分化。相反，缺乏YAP1或其伴系TAZ(WWTR1)的nPSCs在没有XAV939的情况下能有效地抵抗TE分化和自我更新。这些发现解释了人类对tankyrase抑制的不同需求，但在小鼠nPSCs中不需要，并强调了YAP活性在人类幼稚多能性和TE分化中的关键作用。这篇文章有一个相关的采访。Tankyrase抑制抑制滋养外胚层的诱导以稳定人类幼稚多能干细胞。这种作用是通过稳定Angiomotin来限制YAP活性来实现的。
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 interview. Tankyrase inhibition suppresses trophectoderm induction to stabilise human naïve pluripotent stem cells. This effect is mediated by stabilising angiomotin to restrict YAP activity.
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DOI：
10.1242/dev.167833
发表时间：
2018-11-09
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Boroviak T;Stirparo GG;Dietmann S;Hernando-Herraez I;Mohammed H;Reik W;Smith A;Sasaki E;Nichols J;Bertone P
通讯作者：
Bertone P
影响因子：
23.9
作者：
Martello, Graziano;Sugimoto, Toshimi;Diamanti, Evangelia;Joshi, Anagha;Hannah, Rebecca;Ohtsuka, Satoshi;Goettgens, Berthold;Niwa, Hitoshi;Smith, Austin
通讯作者：
Smith, Austin
影响因子：
9.2
作者：
Hirate, Yoshikazu;Hirahara, Shino;Inoue, Ken-ichi;Suzuki, Atsushi;Alarcon, Vernadeth B.;Akimoto, Kazunori;Hirai, Takaaki;Hara, Takeshi;Adachi, Makoto;Chida, Kazuhiro;Ohno, Shigeo;Marikawa, Yusuke;Nakao, Kazuki;Shimono, Akihiko;Sasaki, Hiroshi
通讯作者：
Sasaki, Hiroshi
影响因子：
3.3
作者：
Cox CM;Mandell EK;Stewart L;Lu R;Johnson DL;McCarter SD;Tavares A;Runyan R;Ghosh S;Wilson JM
通讯作者：
Wilson JM
影响因子：
23.9
作者：
Kinoshita M;Barber M;Mansfield W;Cui Y;Spindlow D;Stirparo GG;Dietmann S;Nichols J;Smith A
通讯作者：
Smith A