Embryonic expression of Dlx5/6 (shown here by β-galactosidase staining) in a wild-type mouse at embryonic day 11.5. Image courtesy of Thomas Lufkin, Mount Sinai School of Medicine, USA. Reproduced with permission from Robledo et al. Genes & Development © (2002) Cold Spring Harbor Laboratory Press.

We're reminded almost daily that we are more like our winged, fruit-craving little friends than appearances might first suggest. The latest knock to our dignity comes from Raymond Robledo and colleagues, who have found that a family of genes homologous to those that control the outgrowth of antennae and legs in Drosophila also patterns limbs in mammals. The Distal-less ( Dll )/Dlx family of homeobox transcription factors are known for being involved in limb formation in many insects and vertebrates; the importance of this study has been to extend this function to mammals as well, including humans.

In Drosophila, there is only one Dll gene; flies without it lack the distal portion of their appendages. Mammals, by contrast, have six Dlx genes (Dlx1–Dlx6), which cluster in pairs on the genome — Robledo et al. concentrate here on the Dlx5/6 cluster. This is because, although all vertebrate Dlx genes are expressed in the developing limbs, the brain and the craniofacial primordia, the Dlx5/6 cluster also maps to a region on human chromosome 7 that is associated with a severe human limb defect called split-hand/foot malformation type 1 (SHFM1). In this dominantly inherited disorder, the central limb digits are missing, giving the extremities a claw-like appearance. The phenotype of Dlx5/6 double-knockout mice, which these authors generated, confirm their expectation that Dlx5/6 might regulate limb development. Not only do these animals have bone, inner ear and severe craniofacial defects — as could be predicted from the expression patterns of Dlx5/6 and as has been reported for other Dlx single- and double-knockout mice — but they also phenocopy the limb defects seen in human SHFM1.

However, Dlx genes can only be said to be functional homologues of Dll if the limb abnormalities of Dlx5/6−/− mice arise from defects in proximal–distal (P/D) patterning. Indeed, by embryonic day 11.5 — when most of the mutant defects become apparent — all the molecular markers for the distal medial limb are missing. The authors propose that, by reducing cell proliferation, the absence of Dlx5/6 causes loss of cells in the apical ectodermal ridge (AER), which controls P/D patterning. Furthermore, the ectopic expression of Dlx5 (alone) in the AER fully rescued the SHFM1 defect in Dlx5/6−/− mice.

Putting all this information together, Robledo and colleagues argue that all species with appendages owe these structures to the evolutionary ancient Dll/Dlx gene family. By showing that Dlx5/6 mutant mice can phenocopy SHFM1, they have extended the function of Dlx genes to humans, as well as creating a model for investigating the physiological basis and progression of this human limb abnormality.