Fig. 7. The neural tube gene regulatory network. (A) Selective cross-repressive interactions contribute to the spatial-temporal regulation of gene expression in the neural tube. (Upper panel) Cross-repression between Nkx6 and Dbx proteins generate distinct gene expression patterns in p0, p1 and p2 domains of progenitors. (Lower panel) The generation of p2, pMN and p3 domains depends on selective cross-repressive interactions between Pax6 and Nkx2.2, and Olig2 and Irx3, and on the repression of Olig2 by Nkx2.2. (B) Schematic of DV patterning through repressive interactions. Representative transverse sections through mouse spinal cord are shown (RF, roof plate; FP, floor plate). The identification of regulatory modules that contain binding sites for POU, Sox and HD transcription factors adjacent to many genes of the neural tube GRN has led to a model for the regulation of these genes. POU (green) and Sox (blue) factors are transcriptional activators that are broadly expressed in neural progenitors (bottom panel, green), thus they are believed to provide spatially unrestricted activation to the regulatory modules. The HD factors (red), which have spatially and temporally restricted expression patterns in neural progenitors (example in bottom panel), mostly function as transcriptional repressors and have therefore been proposed to provide repressive input to the modules. The combination of uniform positive input and spatially restricted negative input on a target gene (yellow) would generate a spatially restricted pattern of expression (bottom panel). In this model, the consequences of mutating the repressive HD gene would be the derepression of the target gene (bottom panel, right). (C) Alterations in the pattern of gene expression in embryos lacking individual members of the neural tube GRN confirm the importance of cross-repressive interactions for DV pattern formation. The changes in gene expression in mouse embryos mutant for the indicated genes are summarized in the diagrams. In Nkx6.1^-/- embryos, Nkx6.2 (6.2) and Dbx2 (D2) are expressed in more-ventral progenitors. Dbx1 (D1) expands ventrally in Nkx6.2^-/- mutants. Deletion of both Nkx6.1 and Nkx6.2 results in the ventral expansion of both Dbx1 and Dbx2. In Olig2^-/- mouse embryos, Irx3 expands into the domain normally occupied by MN progenitors. Olig2 (O2) expands ventrally in Nkx2.2^-/- embryos. In embryos mutant for Pax6, Nkx2.2 (2.2) expands dorsally, repressing Olig2 expression (Irx3 expression has not been determined).