Fig. 4. Signalling molecules that affect Hox gene expression along the AP axis. An E8.5 (10 pairs of somites) stage mouse embryo, showing the hindbrain and spinal cord in the neural tube, and the occipital and trunk somites in the paraxial mesoderm. The distribution of RA is indicated in blue. RA is synthesized by Raldh2 in the somites. Anteriorly, RA diffuses into the hindbrain, where the Hox genes are differentially sensitive to RA. For example, rhombomeres (r) 3 and 4, where RA concentration is low, express only the most 3' Hox genes; r6 to r8 express the 3' plus more 5' Hox genes. Posteriorly to somite levels, the concentration of diffusing RA decreases more sharply because of the activity of a RA-degrading enzyme, Cyp26 (see red double-headed arrow, which also shows the extent of the presomitic mesoderm). Other signalling molecules present posteriorly are Wnt (not shown) and Fgf. Fgf signals (orange/yellow) are abundant around the node region and decrease gradually to fade out in the neurectoderm and in the mesoderm at the level of the last-formed somite. The node region and its nearby pool of stem cells (see Fig. 3) are exposed to high Fgf concentrations. The mesoderm and neurectoderm cells exposed to low Fgf concentrations are maturing. As the axis extends, `younger' cells come to experience this decreasing Fgf concentration.