Canonical Wnt signals have been implicated in multiple events during early embryogenesis, including primary axis formation, neural crest induction, and A-P patterning of the neural plate. The mechanisms by which Wnt signals can direct distinct fates in cell types that are closely linked both temporally and spatially remains poorly understood. However, recent work has suggested that the downstream transcriptional mediators of this pathway, Lef/Tcf family DNA binding proteins, may confer distinct outcomes on these signals in some cellular contexts. In this study, we first examined whether inhibitory mutants of XTcf3 and XLef1 might block distinct Wnt-dependent signaling events during the diversification of cell fates in the early embryonic ectoderm. We found that a Wnt-unresponsive mutant of XTcf3 potently blocks neural crest formation, whereas an analogous mutant of XLef1 does not, and that the difference in activity mapped to the C-terminus of the proteins. Significantly, the inhibitory XTcf3 mutant also blocked expression of markers of anterior-most cell types, including cement gland and sensory placodes, indicating that Wnt signals are required for rostral as well as caudal ectodermal fates. Unexpectedly, we also found that blocking canonical Wnt signals in the ectoderm, using the inhibitory XTcf3 mutant or by other means, dramatically expanded the size of the neural plate, as evidenced by the increased expression of early pan-neural markers such as Sox3 and Nrp1. Conversely, we find that upregulation of canonical Wnt signals interferes with the induction of the neural plate, and this activity can be separated experimentally from Wnt-mediated neural crest induction. Together these findings provide important and novel insights into the role of canonical Wnt signals during the patterning of vertebrate ectoderm and indicate that Wnt inhibition plays a central role in the process of neural induction.

The neural crest, a cell type found only in vertebrate embryos, gives rise to the structures of the skull and face and most of the peripheral nervous system, as well as other cell types characteristic of vertebrates. These cells are of great clinical significance and a wide variety of congenital defects are due to aberrant neural crest development. Increasing numbers of studies are contributing to our understanding of how this group of cells form and differentiate during normal development. Wnt, FGF, BMP, and Notch-mediated signals all have essential roles in this process, and several of these signals appear to play multiple temporally distinct roles. Changes in the response of neural crest cells to the same signal over time may be mediated, in part, by an ever-changing cocktail of transcription factors expressed within these cells. Neural crest development is thus a complex multistep process, and elucidating the molecular mechanisms that mediate distinct aspects of this process will require that we determine the role of each of these factors alone and in combination. Here, we review some recent advances in our understanding of the signals and downstream transcription factors involved in neural crest cell formation.

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