Fgf8a induces neural crest indirectly through the activation of Wnt8 in the paraxial mesoderm

Abstract

Two independent signals are necessary for neural crest (NC) induction in Xenopus: a Bmp signal, which must be partially attenuated by Bmp antagonists, and a separate signal mediated by either a canonical Wnt or an Fgf. The mesoderm underlying the NC-forming region has been proposed as a source of this second signal. Wnt8 and Fgf8a are expressed in this tissue around the time of NC induction and are therefore good candidate NC inducers. Loss-of-function studies indicate that both of these ligands are necessary to specify the NC; however, it is unclear whether these signaling molecules are operating in the same or in parallel pathways to generate the NC. Here, we describe experiments addressing this outstanding question. We show that although Wnt8 expression can restore NC progenitors in Fgf8a-deficient embryos, Fgf8a is unable to rescue NC formation in Wnt8-depleted embryos. Moreover, the NC-inducing activity of Fgf8a in neuralized explants is strongly repressed by co-injection of a Wnt8 or a β-catenin morpholino, suggesting that the activity of these two signaling molecules is linked. Consistent with these observations, Fgf8a is a potent inducer of Wnt8 in both whole embryos and animal explants, and Fgf8a knockdown results in a dramatic loss of Wnt8 expression in the mesoderm. We propose that Fgf8a induces NC indirectly through the activation of Wnt8 in the paraxial mesoderm, which in turn promotes NC formation in the overlying ectoderm primed by Bmp antagonists.

Signaling pathways and tissue interactions in neural plate border formation

“…FGFs have been shown to sensitize the dorsal ectoderm to respond to BMP inhibition, transcriptionally regulate BMPs and Wnts, and to contribute directly to NPB specification. 19,20,[54][55][56] In Xenopus, the DLMZ expresses a number of paracrine growth factors at the onset of gastrulation including wnt8, fgf4, fgf8, gdf6 and the BMP antagonist chordin (Fig. 2) and further expresses hairy2, fgfr1, fgfr4a, bmpr1a, pcns and ror2.…”

The Proto-oncogene Transcription Factor Ets1 Regulates Neural Crest Development through Histone Deacetylase 1 to Mediate Output of Bone Morphogenetic Protein Signaling

“…4, M-O). To exclude the possibility that the repression of NC was due to defective mesoderm formation (45,46), we examined the expression of two mesoderm marker genes, brachyury and chordin, in ets1-injected embryos. The expression of brachyury and chordin was not obviously altered by ectopic ets1 (Fig.…”

Wnt Signaling in Vertebrate Axis Specification

“…These observations indicate that Wnt signaling plays different roles in axis specification at different developmental stages. Several Wnt ligands, including Wnt3a, Wnt5a, Wnt8, and Wnt11, are expressed in the ventral or posterior region of the embryo (Christian et al 1991a;Krauss et al 1992;Moon et al 1993;Kelly et al 1995;Hong et al 2008). On the other hand, multiple Wnt antagonists, such as Frzb/Sfrp3, Crescent, Shisa, and Dkk1, are expressed in the head region (Leyns et al 1997;Wang et al 1997;Glinka et al 1998;Shibata et al 2005;Yamamoto et al 2005).…”

“…For example, FGF8a signaling transcriptionally activates Wnt8 to promote neural crest development (Fig. 3A) (Hong et al 2008). Alternatively, two pathways may function in parallel, when a target promoter contains transcription factor binding sites that are specific for each pathway (Fig.…”