Induction of Paraxial/Somite Fate in NMP-Derived Mesoderm

Although the majority of the NMP-derived mesoderm will become paraxial mesoderm, a subset will become lateral mesoderm such as vascular endothelial cells. This decision is made locally by secreted signaling molecules that pattern the newly formed mesoderm (Figure 5.3). Clonal analysis of single-cell descendants in the mouse embryo showed that NMPs can give rise to lateral mesoderm, in addition to neural and paraxial mesoderm (Tzouanacou et al., 2009). An analysis of the role of canonical Wnt signaling in the zebrafish demonstrated that Wnt signaling not only plays an essential role in inducing mesoderm from NMPs, but also functions within the mesoderm progenitors to pattern them into paraxial and lateral subtypes (Martin and Kimelman, 2012). Continued activation of Wnt signaling leads to paraxial fate, whereas inhibition of Wnt signaling in cells just after they have become mesoderm causes them to adopt a vascular endothelial fate.

In addition to Wnt signaling, BMP and FGF signaling also play critical roles in patterning newly formed mesoderm. FGF signaling, like Wnt signaling, promotes paraxial fate, whereas BMP signaling induces lateral fates (Row et al., 2018). In the absence of FGF signaling, cells that would normally become paraxial mesoderm and somites instead become vascular endothelium. In the absence of BMP signaling, those NMP-derived mesodermal cells that would normally become vascular endothelium adopt a paraxial fate at the ventral midline (just under the notochord) where vasculogenesis normally occurs. These transfated cells also segment into somites with the same periodicity as the somites that normally form, and they differentiate into skeletal muscle. In the absence of both FGF and BMP signaling, newly derived mesoderm adopts an endothelial fate, suggesting that this is the default fate of NMP-derived mesoderm with respect to these two signals. BMP is required for endothelial fate to counteract the FGF and Wnt signals that are present initially during the mesoderm induction and EMT process. The patterning of the mesoderm downstream of FGF and BMP signaling is at the level of bHLH transcription factor activity. FGF signaling activates the expression of bFILH transcription factors msgnl, myf5, and myod, which in turn are required for the paraxial fate. In the absence of these three transcription factors, NMP-derived mesoderm becomes vascular endothelium. BMP signaling on the other hand induces the expression of the inhibitor of DNA binding (Id) genes, which are HLH proteins that act as natural dominant negative inhibitors of bHLFI proteins. Thus, BMP signaling can antagonize the effects of FGF signaling by inhibiting the FGF-induced bHLFI transcription factors (Row et al., 2018). This patterning mechanism is conserved in both zebrafish and mouse. In vitro-derived mouse NMPs that become mesoderm will give rise to paraxial fates in the presence of FGF signaling, or lateral endothelial fates in the presence of either BMP signaling or induced expression of the ID1 HLH protein (Row et al., 2018). Thus, it is a conserved vertebrate trait that NMP-derived mesoderm must be patterned properly into paraxial mesoderm by FGF and Wnt signaling, the same signals that act as the determination wavefront in the clock and wavefront mechanism of somitogenesis.

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