Fig. 7. The Hox-RAR feedback circuit. Cartoon shows the Hox-responsive enhancers (HOX, green) and RA-responsive enhancers (RARE, blue) from Rarb (top), Hoxb4 (middle) and Hoxd4 (bottom). Enhancer-promoter interactions (black arrows), transcription and translation (unfilled arrows), and transcriptional regulation by Hoxb4 and Hoxd4 proteins (green arrows) and RARs (blue arrows) are shown. The external RA signal that initiates this neural genetic circuit (red arrow) is synthesized by Raldh2 in the adjacent mesoderm. A functional equivalent of the LNE/distal enhancer (HOX element with broken outline) has, thus far, not been identified for Hoxd4 (Nolte et al., 2003). The correct positioning of the single or multiple transcription start sites of each gene has been omitted for clarity. The central importance of the HoxRARß interactions described in this study are emphasized with thick green arrows. This figure also summarizes genetic interactions identified in several other published studies (see text for details).