BMP4 Signaling Acts via Dual-Specificity Phosphatase 9 to Control ERK Activity in Mouse Embryonic Stem Cells

Abstract

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.

Design of stapled α-helical peptides to specifically activate Wnt/β-catenin signaling

“…Although Wnt3a alone could slightly reverse the neural differentiation process, Wnt3a plus SAHPA1 efficiently promoted self-renewal and inhibited differentiation of mESCs, as shown by colony morphology and alkaline phosphatase (AP) staining ( Figure 1I). This observation was further supported by examining the expression of the pluripotency markers -Pou5f1 (Oct4), Nanog, and Rex1, and the neural markers -Sox1 and nestin [10]. Upon the withdrawal of LIF and BMP4, the expression of these pluripotency markers was significantly decreased and the expression of the neural markers was significantly increased ( Figure 1J).…”

X-chromosome dosage as a modulator of pluripotency, signalling and differentiation?

“…Through the activation of Mek and Erk, Fgf4 leads to the downregulation of Nanog at the transcriptional level, but also destabilizes Klf2 and Klf4 protein through Erk-dependent phosphorylation [22,23]. Moreover, Gsk3, which can mediate Wnt signalling has a differentiation promoting effect by repressing several pluripotency factors, [14], c [15], d [16], e [17], f [18], g [19], h [20], i [21], j [22], k [23], l [24], m [25], n [26], o [27].…”

Inhibition of Transforming Growth Factor β (TGF-β) Signaling can Substitute for Oct4 Protein in Reprogramming and Maintain Pluripotency

“…5C). The BMP pathway can suppress FGF/MEK/ERK signaling through Smad1/5/8 in mouse ES cells (44). Therefore, the levels of phosphorylate Smad1 (p-Smad1), an indicator of BMP signaling activity, were detected.…”