Making HoxD waves

When developmental biologists first got their hands on DNA, perhaps the most remarkable finding was that the order of genes on the chromosome reflected the genes' time and location of expression. Genes at the tail end of each cluster were expressed proximally and early; those at the front of the cluster were expressed distally and later. Now, Basile Tarchini and Denis Duboule (University of Geneva, Switzerland) find that simple placement of two gene regulatory elements explains the entire expression sequence for the HoxD cluster, which patterns forelimb development.

Two waves of HoxD expression control limb formation in vertebrates: an early wave, which generates proximal structures such as the forearm, and a later wave, which forms distal structures such as digits. By breeding mouse strains with targeted meiotic recombinations, Duboule and colleagues created deletions and reduplications of the Hoxd genes, and they looked for changes in regulation.

Earlier work by the group showed that the later wave of digit development is controlled by a positive regulatory element located outside the HoxD cluster. Analysis of the 19 strains of mice generated for this study identified a different mechanism for the forelimb, in which gene expression is regulated by a positive and a negative regulator, each located on either side of the cluster. The asymmetry in HoxD expression is thus simply a factor of a gene's relative distance from the positive or negative influence, and the balance between the two forces.

The group is now applying the same technique to tease out the trunk patterning mechanism, a more complicated endeavor because many more genes are involved. “But we have good evidence that it's quite close to the one that's organizing the proximal limbs,” he says.

If the similarity holds, it would support the idea that proximal limb structures are phylogenetically much older ones. Duboule proposes that when proximal limbs evolved, nature co-opted the similar trunk patterning mechanism to also regulate limb development. But digit development, which is thought to have occurred about 300 million years ago, required nature to come up with a new approach.

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