Molecular regulation of neural crest differentiation from embryonic ectoderm

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Fox factors (winged-helix transcription factors) play important roles in early embryonic patterning. We have shown that FoxD3 (formerly, Forkhead 6) is a key regulator of neural crest determination in Xenopus embryos. Expression of FoxD3 in the presumptive neural crest region starts at the late gastrula stage in a manner similar to that of Slug, and overlaps with that of Zic-rl. When overexpressed in the embryo and in ectodermal explants, FoxD3 induces expression of neural crest markers. Attenuation of FoxD3-related signaling by a dominant-negative FoxD3 construct (FoxD3deIN) inhibits neural crest differentiation in vivo without suppressing the CNS marker Sox2. In animal cap explants, neural crest differentiation induced by Slug and Wnt3a is also inhibited by FoxD3delN but not by a dominant-negative form of FoxD1. Loss-of-function studies using dominant-negative forms of FoxD3 and Slug indicate(A) Slug induction by Zic factors requires FoxD3-related signaling(B) FoxD3 and Slug have distinct downstream pathways that regulate expression of neural crest markers such as Ets-1 and Twist.These data demonstrate that FoxD3 plays an essential role in the upstream regulatory pathway leading to neural crest determination. In addition, we have recently established an efficiently in vitro induction system for neural crest differentiation from mouse ES cells. By using this system, we are currently analyzing detailed gene interactions between early neural crest determination genes.