Fig. 4. Key signals and transcriptional networks regulating NMps.
FGF and Wnt signals provided by the primitive streak and CLE induce the expression of Bra and the Sox2 (N1) enhancer, and Bra in turn promotes Wnt signalling. FGF signalling also promotes expression of Nkx1.2 (Sax1), and this transcription factor in turn induces Fgf8 transcription; it also indirectly promotes Wnt signalling by inhibiting expression of the repressor Tcf3 [indicated with a dotted line as evidence comes from P19 cells (Tamashiro et al., 2012)]. Wnt signalling induces the expression of Cdx genes, which act both to promote Wnt signalling and to regulate caudal Hox gene expression. Sox2 transcription is also repressed by BMP signalling delivered by epiblast cells posterior and lateral to the CLE and so defines the domain within which NMps can arise. The co-expression of Sox2 and Bra is a central feature of NMps and there is some evidence that they are mutually repressive (indicated by dotted inhibition symbols). For example, Sox2 mRNA expression is high in Bra mutant NMps in which Wnt is activated (Gouti et al., 2014); in the frog, T-box genes directly repress Sox2 (Gentsch et al., 2013); and in the mouse the presomitic mesoderm gene Tbx6 represses Sox2 via the N1 enhancer (Li and Storey, 2011; Takemoto et al., 2011). Conversely, Sox2 N1 loss (in a Sox3 null background) increases the ingression of cells to form presomitic mesoderm (Yoshida et al., 2014), suggesting that Sox2 normally restrains this Bra-induced activity; Sox2 also binds the Bra promoter in ESC-derived neural progenitors and Sox2 overexpression represses Bra in a Wnt-driven mesodermal differentiation assay (Zhao et al., 2004; Thomson et al., 2011). This mutual repression between Sox2 and Bra might underpin the creation of a state in which cells are poised to adopt either neural or mesodermal cell fate.