Three models have been suggested to explain the mechanism in which RA regulates Hox gene expression (Figure 2). In the first model retinoic acid directly regulates Hox gene expression by binding RA to RAREs in the enhancer region of a Hox gene. RARE elements have been located in enhancers downstream from the murine Hox-a1 and human HoxA1 genes, and the murine and chicken Hox-b1 genes. RAR g is thought to activate the Hox-a1 gene in response to RA in the teratocarcinoma cells (Langston and Gudas, 1994). A second model supports the idea that one RARE coordinates the expression of several other Hox genes. The reduction in shading of the figure below depicts the notion that Hox gene activation by retinoic acid is gradient dependent. A higher concentration of retinoic acid is required to activate equivalently a gene near the 5' end than is required at the 3' end. The third model depicts the initiation of a cascade of gene activation of Hox proteins beginning with the activation of one 3' retinoic acid responsive enhancer. Each gene activates the adjoining gene on the 5' side and the Hox genes are thus activated sequentially (Langston and Gudas, 1994).
Figure 2: Models describing possible mechanisms for the activation of Hox gene clusters by retinoic acid. (from Langston and Gudas, 1994)
At the time the Langston and Gudas paper was published, it was still believed that a retinoic acid gradient may be controlling directly the expression of Hox genes, especially that of the Hox-d genes which are expressed around the zone of polarizing activities (ZPA) in the limb. It has since been determined that sonic hedgehog, a vertebrate homologue of the Drosophila segment polarity gene hedgehog , is the molecule made in the ZPA which coordinates the development of the anterior-posterior axis (Scott Gilbert, Personal Communication). Retinoic acid, however, coordinates its function with sonic hedgehog, and helps the functioning of the gene. The Bone Morphogenic Protein 2 (BMP2) also aids in the functioning of sonic hedgehog. Research is now being done to identify and elucidate the nature of the targets of the Hox genes.