FIGURE 8.

Establishment of the ANZ by the WNT-BMP-FGF regulatory network. In this model, WNT3A and BMP signaling antagonistically regulate Fgf8 expression and consequently cell death. WNT3A induces the expression of Fgf8 in the AER. BMP signaling inhibited Fgf8 expression; meanwhile, DKK inhibits the function of WNT/ß catenin signaling, and consequently, the expression of Fgf8 is inhibited. In the presumptive ANZ, the high levels of FGF8 from AER are necessary for cell survival, but FGF8 is also required for promoting cell death regulating Bmp4 and Dkk expression. The establishment of ANZ occurs when the levels of FGF signaling are reduced and BMP signaling increases leading to the inhibition of Fgf8 in the AER inducing cell death. Fgfr1, Fgfr2, Mkp3, Churchill, Msx2, Id2, and Bambi are expressed differentially in the presumptive ANZ and the established ANZ.