The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Cell Stem Cell. 2012 Feb 3;10(2):171-82. doi: 10.1016/j.stem.2011.12.016.
Extrinsic BMP and LIF signaling collaboratively maintain mouse embryonic stem cell (ESC) pluripotency, whereas appropriate ERK activity is essential for ESC fate commitment. However, how the extrinsic signals restrain appropriate ERK activity remains elusive. Here, we show that, whereas LIF sustains relatively high ERK activity, BMP4 can steadily attenuate ERK activity by upregulating ERK-specific dual-specificity phosphatase 9 (DUSP9). This upregulation requires Smad1/5 and Smad4 and specifically occurs to DUSP9, but not other DUSPs, and only in ESCs. Through DUSP9-mediated inhibition of ERK activity, BMP signaling reinforces the self-renewal status of mouse ESCs together with LIF. Upon LIF withdrawal, ESCs spontaneously undergo neural differentiation, during which process DUSP9 can partially mediate BMP inhibition on neural commitment. Collectively, our findings identify DUSP9 as a critical mediator of BMP signaling to control appropriate ERK activity critical for ESC fate determination.
外在的 BMP 和 LIF 信号协同维持小鼠胚胎干细胞（ESC）的多能性，而适当的 ERK 活性对于 ESC 命运决定至关重要。然而，外在信号如何抑制适当的 ERK 活性仍然难以捉摸。在这里，我们表明，虽然 LIF 维持相对较高的 ERK 活性，但 BMP4 通过上调 ERK 特异性双特异性磷酸酶 9（DUSP9）可以稳定地减弱 ERK 活性。这种上调需要 Smad1/5 和 Smad4，并且特异性地发生在 DUSP9 上，而不是其他 DUSPs 上，并且仅在 ESCs 中发生。通过 DUSP9 介导的 ERK 活性抑制，BMP 信号与 LIF 一起增强了小鼠 ESCs 的自我更新状态。在 LIF 撤出后，ESCs 会自发地进行神经分化，在此过程中，DUSP9 可以部分介导 BMP 对神经分化的抑制作用。总之，我们的发现确定了 DUSP9 作为 BMP 信号的关键介质，可控制适当的 ERK 活性，这对于 ESC 命运决定至关重要。
