In the limb, a gradient of retinoic acid along the anterior-posterior axis may activate specific homeotic genes in particular cells. The concept that all developing and regenerating vertebrate limbs use the same mechanism for limb growth and pattern formation has only been developed recently. Evidence for a common mechanism of limb development includes the same pattern of development in new and regenerating limbs and of limbs across the vertebrate species. Different vertebrate species respond similarly to experiments where limbs are amputated and parts are removed along the proximal-distal axis. Grafts combining the developing and regenerating parts of limb buds will interact to create supernumerary limbs where the contribution of the developing and regenerating limb cells cannot be distinguished from the other as shown below.
Figure 1: Diagram depicting the indistinguishable development of a supernumery limb from a graft of developing and regenerating parts of limb (from Bryant and Gardiner, 1992)
Developing and regenerating limbs also use the same mechanism of growth: the anterior posterior organization of the limb is maintained whether or not the limb is budding for the first time or regenerating, and the same genes are expressed in both types of growth. Differences between the two types of growth occur only in areas which are not affected by the factors which control the pattern formation. These all support that limb formation occurs similarly throughout the vertebrates (Bryant and Gardiner, 1992).
The limb has been one of the most extensively studied structure due to the ability to mutate its normal growth but not kill the embryo. Evidence linking retinoic acid to limb growth was first discovered when the addition of all-trans RA to the anterior portion of the chick wing bud led to an expansion of the Hox D gene cluster normally expressed only in the posterior part of the limb to be expressed in the anterior part of the limb as well. This experiment indicated that retinoic acid was activating genes of the Hox D genes where they would not normally be expressed.
Retinoic acid has been found to direct and disrupt the development of the pattern in many different invertebrate and vertebrate species. Evidence continues to accumulate that retinoic acid plays a large role in regulating the expression of Hox genes, and thus effect the developing pattern in an embryo. While the mechanism is acknowledged to be similar across different vertebrate species, little is known about the functions of the targets of retinoic acid, particularly the Hox genes. This is one area in which research appears to be directed