Neural Tube Formation and Patterning

How do these morphogens ultimately confer positional information to cells in the neural tube? Recall that progenitor identity is determined by the unique gene regulatory network it expresses. The system of differential gene expression a cell can exhibit is dependent on the combination of its distance from, and duration of, exposure to the morphogenetic signaling centers. Cells adjacent to the floor plate that receive high concentrations of Sonic hedgehog synthesize the transcription factors Nkx6-1 and Nkx2-2 and become the ventral (V3) interneurons. The cells dorsal to them, exposed to slightly less Sonic hedgehog (and slightly more TGF-β), produce Pax6 and Olig2 and become motor neurons. The next two groups of cells, receiving progressively less Sonic hedgehog, express Pax6 alone and become the V2 and V1 interneurons. Finally, the cells at the dorsalmost segment of the neural tube express Pax7 and become dorsal progenitors (see Figure 1; Lee and Pfaff 2001; Muhr et al. 2001).

It had been thought that the intersecting gradients of Shh and TGF-β signals would be sufficient to instruct the synthesis of the various transcription factors, but the regulatory network is far more complex and appears to integrate both spatial and temporal distributions of morphogen signaling. If Pax7-expressing intermediate neural tube explants are exposed to increasing concentrations of Shh, they will stop expressing Pax7 and will express Olig2 and Nkx2-2 in a dose-dependent manner (Figure 1A). If these same explants are exposed to a constant concentration of Shh over an extended period of time, they first express Olig2, followed by increasing levels of Nkx2-2 expression (Figure 1B, C). These results support a model in which the concentration of Shh and the duration of Shh signaling together induce differential gene expression and cell fate patterning in the neural tube (Dessaud et al. 2007). The interpretation of these results is based on certain assumptions about the concentrations and duration of Shh signaling in the embryo, however, and, as is often the case, the process may prove to be more complex. (See Further Development 13.8, Transcriptional Cross-Repression by the Downstream Shh and TGF-β Effector Proteins, and Further Development 13.9, Gli Activation, both online.)

Figure 1 Neural tube gene expression responds to both concentration and duration of Shh. (A) The expression of three defining transcription factors—Pax7 (dorsalmost, blue), Olig2 (ventromedial, red), and Nkx2-2 (ventralmost, green)—are shown in a transverse section of the chick neural tube. Intermediate neural tube explants express Pax7 in the absence of Shh; when Shh is applied in increasing doses, however, Pax7 is lost, and Olig2 and Nkx2-2 are induced in a dose-dependent manner. This result suggests that Shh represses Pax7 while inducing Olig2 and Nkx2-2. It is known that Nkx2-2 also represses Olig2 transcription. (B) Initial exposure of intermediate neural tube explants to 4 nM Shh results in only Olig2 expression, yet over longer exposure times, Nkx2-2 expression becomes progressively induced. These data are quantified in (C). (From E. Dessaud et al. 2007. Nature 450: 717–720.)

Literature Cited

Dessaud, E., L. L. Yang, K. Hill, B. Cox, F. Ulloa, A. Ribeiro, A. Mynett, B. G. Novitch and J. Briscoe. 2007. Interpretation of the Sonic hedgehog morphogen gradient by a temporal adaptation mechanism. Nature 450: 717–720.
PubMed Link

Lee, S.-K. and S. L. Pfaff. 2001. Transcriptional networks regulating neuronal identity in the developing spinal cord. Nat. Neurosci. Suppl. 4: 1183–1191.
PubMed Link

Muhr, J., E. Andersson, M. Persson, T. M. Jessell and J. Ericson. 2001. Groucho-mediated transcriptional repression establishes progenitor cell pattern and neuronal fate in the ventral spinal cord. Cell 104: 861–873.
PubMed Link

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