Extrinsic BMP and LIF signaling collaboratively maintain mouseembryonicstem cell (ESC) pluripotency, whereas appropriate ERKactivity is essential for ESC fate commitment. However, how the extrinsic signals restrain appropriate ERKactivity remains elusive. Here, we show that, whereas LIF sustains relatively high ERKactivity, BMP4 can steadily attenuate ERKactivity by upregulating ERK-specific dual-specificityphosphatase9 (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 ERKactivity, 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 ERKactivity critical for ESC fate determination.

Li ZW, Fei T, Zhang JP, Zhu GY, Wang L, Lu DY, Chi XC, Teng Y, Hou N, Yang X, Zhang HQ, Han JDJ, Chen YG*. (2012) BMP4 Signaling Acts via Dual-Specificity Phosphatase 9 to Control ERK Activity in Mouse Embryonic Stem Cells. Cell Stem Cell, 10(2):171-182.