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    • We obtained some evidence that NMD

    2018-10-20

    We obtained some evidence that NMD not only influences hESC fate through TGF-β and BMP signaling, but also through the WNT, FGF, and NOTCH pathways (Figure 2E). This raises the possibility that the ability of NMD to influence 5-lipoxygenase and mesoderm differentiation is a combinatorial process amplified by its ability to act through several signaling pathways. As a further level of complication, NMD may act at several differentiation steps. The differentiation of definitive endoderm and mesoderm from hESCs requires an initial commitment to the mesendodermal cell lineage (Sui et al., 2013). Commitment to this intermediate cell fate is promoted by FGF, WNT, BMP, and TGF-β signaling (Loh et al., 2014). After hESCs reach the mesendoderm stage, their subsequent development into mesoderm or endoderm further depends on the local signaling milieu. TGF-β and FGF signaling promote differentiation into definitive endoderm, while BMP and WNT signaling elicit differentiation into mesoderm (Loh et al., 2014). Given our evidence that NMD influences all these signaling pathways, it would not be surprising if NMD magnitude affects several of these differentiation steps, including the initial generation of mesendoderm. We note that while some definitive endoderm markers regulated by NMD (MIXL1 and EOMES) are also expressed by mesendoderm, other markers regulated by NMD are considered specific for definitive endoderm or mesoderm (SOX17/CXCR4 and BRACHYURY/HAND1, respectively) (Izumi et al., 2007). NMD may act in two non-mutually exclusive ways to influence hESC cell fate. First, NMD may serve as a switch that cooperates with transcriptional mechanisms to drive hESC differentiation. This follows from the fact that simultaneous transcriptional activation and mRNA stabilization elicit more dramatic increases in steady-state mRNA level than either of these processes alone. For example, our results suggest that activin-triggered transcriptional induction coupled with NMD suppression would increase not only the synthesis but also the stability of mRNAs encoding pro-endoderm differentiation proteins, thereby driving robust endoderm differentiation. Second, NMD may reinforce cell-fate decisions in the face of genetic or environmental perturbation. This follows from our finding that extracellular signals triggering a given cell fate alter the magnitude of NMD to reinforce that particular cell fate. For example, we found that activin treatment suppresses NMD magnitude (Figure 1B) which, in turn, leads to upregulation of mRNAs encoding pro-TGF-β factors (Figure 3A). This would further stimulate TGF-β signaling and strongly drive endoderm differentiation. Our results suggest that a similar feedback mechanism involving the WNT signaling pathway may exist (Figure 6). Finally, our results imply that NMD allows for subtle responses to morphogen gradients. For example, NMD specifically modulates hESC fate in response to high activin doses but not low activin doses (Figure 4). If confirmed in vivo, this indicates an extra layer of developmental control whereby the magnitude of NMD can trigger different cell fates that depend on the local morphogen milieu. Our finding that NMD has inverse effects on hESC endoderm and mesoderm differentiation differs from what was recently reported for mouse ESCs (mESCs). Li et al. (2015) found that loss or depletion of NMD factors in mESC blocks their differentiation into all three primary germ layers. Because these authors depleted several different NMD factors, including UPF1, which we also depleted, we regard it as unlikely that the different findings of our two studies are due to NMD branch-specific effects or non-NMD functions of NMD factors. Instead, a more likely explanation is that mESCs and hESCs differ with regard to their responses to NMD. This may stem from the fact that mESCs and hESCs exhibit intrinsic species-specific differences in factor requirements and expression patterns (Blair et al., 2011; Moon et al., 2006). In addition, recent studies have identified differences in lineage-specific markers originally thought to be conserved between mouse and human (Blakeley et al., 2015), as well as differences between mESC and hESC differentiation programs (Moon et al., 2006). As an example of the latter, while both the FGF and WNT pathways govern primate primitive endoderm versus epiblast cell fate, only FGF acts in the equivalent pathway in rodents (Boroviak et al., 2015). Our evidence that NMD regulates both WNT and FGF signaling (Figures 2E, 3A, and 3B) may partly explain NMD\'s differential effects on hESCs and mESCs. These studies highlight the need to perform research on human pluripotent cells, which often behave differently from mouse pluripotent cells.