Yap is the key effector of Hippo signaling; however, its role in embryonic stem cells (ESCs) remains controversial. Here, we identify two Yap splicing isoforms (Yap472 and Yap488), which show equal expression levels but heterogeneous distribution in ESCs. Knockout (KO) of both isoforms reduces ESC self-renewal, accelerates pluripotency exit, but arrests terminal differentiation, while overexpression of each isoform leads to the reverse phenotype. The effect of both Yap isoforms on self-renewal is Teads-dependent and mediated by c-Myc. Nonetheless, different isoforms are found to affect overlapping yet distinct genes, and confer different developmental potential to Yap-KO cells, with Yap472 exerting a more pronounced biological effect and being more essential for neuroectoderm differentiation. Constitutive activation of Yaps, particularly Yap472, dramatically upregulates p53 and Cdx2, inducing trophectoderm trans-differentiation even under self-renewal conditions. These findings reveal the combined roles of different Yap splicing isoforms and mechanisms in regulating self-renewal efficiency and differentiation potential of ESCs.

中文翻译：

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Yap剪接异构体的表达水平和激活状态决定胚胎干细胞的自我更新和分化潜能

Yap 是 Hippo 信号的关键效应器；然而，它在胚胎干细胞（ESC）中的作用仍然存在争议。在这里，我们确定了两种 Yap 剪接亚型（Yap472 和 Yap488），它们在 ESC 中表现出相同的表达水平但分布不均匀。两种亚型的敲除 (KO) 会减少 ESC 自我更新，加速多能性退出，但会阻止终末分化，而每种亚型的过表达会导致反向表型。两种 Yap 亚型对自我更新的影响依赖于 Teads，并由 c-Myc 介导。尽管如此，发现不同的亚型会影响重叠但不同的基因，并赋予 Yap-KO 细胞不同的发育潜力，Yap472 发挥更显着的生物学效应，对神经外胚层分化更为重要。Yaps的本构激活，特别是Yap472，显着上调 p53 和 Cdx2，即使在自我更新条件下也能诱导滋养外胚层转分化。这些发现揭示了不同 Yap 剪接异构体和机制在调节 ESC 自我更新效率和分化潜能中的综合作用。