Living Systems Institute, University of Exeter, Stocker Road, Exeter EX4 4QD, UK.
Bioimaging Centre, Department of Biosciences, University of Exeter, Stocker Road, Exeter EX4 4QD, UK.
Development. 2022 Dec 15;149(24). doi: 10.1242/dev.200988. Epub 2022 Dec 21.
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.
人幼稚多能干细胞（nPSCs）的增殖依赖于 MEK/ERK 信号的抑制。然而，MEK/ERK 的抑制也会促进滋养外胚层（TE）的分化。因此，强大的自我更新需要抑制 TE 命运。使用 XAV939 抑制 Tankyrase 已被证明可以稳定人 nPSCs，并与 TE 抑制有关。在这里，我们剖析了这种效应的机制。Tankyrase 抑制已知会阻断经典的 Wnt/β-catenin 信号。然而，我们表明，耗尽β-catenin 的 nPSCs仍然依赖于 XAV939。我们发现，XAV939 并没有抑制 Wnt，而是通过减少 TE 诱导转录因子 TEAD 的共激活因子 YAP 的激活来防止 TE 的诱导。Tankyrase 抑制稳定了血管生成素，从而限制了 YAP 的核积累。在删除血管生成素家族成员 AMOT 和 AMOTL2 后，核 YAP 增加，XAV939 无法阻止 TE 的诱导。组成性激活的 YAP 的表达也同样引发 TE 分化。相反，缺乏 YAP1 或其同源物 TAZ（WWTR1）的 nPSCs有效地抵抗 TE 分化和自我更新，而无需 XAV939。这些发现解释了 Tankyrase 抑制在人 nPSCs 中而不是在鼠 nPSCs 中的独特需求，并强调了 YAP 活性在人幼稚多能性和 TE 分化中的关键作用。本文有一个相关的“论文背后的人物”采访。
