Fig. 8. Establishment of the spatial relationships of mes-met genes at the Otx2-Gbx2 border. (A) Expression of Wnt1, Fgf8 and En1 in wild-type, Otx2^hOtx1/hOtx1, Gbx2^–/– and Gbx2^–/–; Otx2^hOtx1/hOtx1 embryos at the three- to four-somite and six- to eight-somite stages. Thickness of the bars represents the level of gene expression. (B) Model of how the mes-met genes are induced and how the normal spatial expression of these genes is established in the neuroectoderm. Opposing interactions between posteriorizing and anteriorizing signals determine the position of the Otx2/Gbx2 border, as well as a mes-met competence domain by E7.5. The entire presumptive mes-met region is competent to respond to a signal that induces expression of Wnt1, Fgf8 and other mes-met genes. Expression of Otx2 and Gbx2 in the neuroectoderm at E7.75 subdivides the presumptive mes-met region into two distinct domains. Negative regulation of Wnt1 by Gbx2, and of Fgf8 by Otx2 results in the initial restriction of Wnt1 and Fgf8 expression specifically to the Gbx2- and Otx2-negative positive regions, respectively, at E8.5. At later stages, expression of Wnt1 and Fgf8 is maintained only in cells adjacent to each other through mutual positive feedback between Fgf8 and Wnt1 (or an unknown secreted factor in the midbrain) and between all mes-met genes. Otx2 and Gbx2 continue to negatively regulate Fgf8 and Wnt1 expression, respectively. MHB, mid-hindbrain boundary.

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