Much attention has been devoted to the developing limbs, as early studies performed even before the cloning of RARs have shown (i) that RA applied locally can lead to mirror-image digit duplications in the chick wing bud, thus mimicking ectopic grafts of the posterior 'zone of polarizing activity' (ZPA) ([Tickle, 2006] and references therein); (ii) that endogenous RA is present at high concentrations in the posterior wing bud mesenchyme, which suggested a putative role as a diffusible morphogen [Thaller and Eichele, 1987]. The three Rar genes are expressed during early limb bud development, Rara being ubiquitous, Rarg being found throughout the limb bud mesenchyme before being localized to precartilaginous blastemas, and Rarb being present only in the proximal mesenchyme [Dolle et al., 1989; Smith and Eichele, 1991]. Eventually, it was shown that RA is produced in the flank and proximal limb bud cells by the RALDH2 enzyme, from which it likely acts in conjunction with posteriorly-restricted factors (such as Hand2) to induce a functional ZPA [Mic et al., 2004; Niederreither et al., 2002]. Another, later function of RA concerns the
