The limb buds of the polydactylous mutant embryos, talpid2 and diplopodia-5, possess expanded distal apexes surmounted by prolongated thickened apical ectodermal ridges that promote the outgrowth and formation of digits from both the anterior and posterior mesoderm of the mutant limb buds. The chicken homeobox-containing gene GHox-7 exhibits an expanded domain of expression throughout the expanded subridge mesoderm of the mutant limb buds, providing support for the hypothesis that GHox-7 expression by subridge mesenchymal cells is involved in the outgrowth-promoting effect of the apical ectodermal ridge. During normal limb development GHox-7 is also expressed by the mesoderm in the proximal anterior nonchondrogenic periphery of the limb bud, which includes, but is not limited to the anterior necrotic zone. GHox-7 is also expressed in the posterior necrotic zone at the mid-proximal posterior edge of the limb bud. In contrast, GHox-7 is not expressed in either the proximal anterior or posterior peripheral mesoderm of talpid2 and diplopodia-5 limb buds which lack proximal anterior and posterior necrotic zones. Furthermore, retinoic acid-coated bead implants, which diminish cell death in the anterior necrotic zone, elicit a local inhibition of GHox-7 expression in the proximal anterior peripheral mesoderm. These results support the suggestion that GHox-7 may be involved in defining regions of programmed cell death during limb development. Furthermore, these studies indicate that the distal subridge and proximal anterior nonchondrogenic mesodermal domains of GHox-7 expression are independently regulated.