Quantity is Key for Hox Genes

Like plumbers or carpenters at a construction site, each so-called Hox gene was thought to direct just one task in the assembly of a developing embryo. But in the 13 February Nature, scientists report that at least in some cases, Hox proteins are able to switch jobs with surprising ease. The find will force developmental biologists to reconsider some of their basic assumptions about how certain proteins shape growing tissues.

The Hox genes are famous for their ability to induce monstrous malformations; rearranged in a fruit fly, they can make legs grow in place of antennae. When a particular Hox gene is removed, an embryo develops characteristic flaws. For example, mice missing the Hoxa3 gene have abnormal heads and lack a thymus. On the other hand, mice without Hoxd3 have abnormal skeletons. The disparity of these deformities made sense to scientists, because the Hoxa3 and Hoxd3 proteins are less than 50% alike.

Now it seems that despite their differences, some Hox proteins can stand in for one another. When developmental geneticist Mario Capecchi and his colleagues at the University of Utah in Salt Lake City knocked out Hoxa3 and replaced it with Hoxd3, the mice were normal. The reverse experiment, replacing Hoxd3 with Hoxa3, worked just as well. In both cases, the scientists didn't touch the promoter region, which controls how much protein is made. The team suspects that the amount of protein produced by the promoter is more important than which particular protein gets made.

The find challenges the assumption that slight changes in a protein's structure are entirely responsible for changing its effect on development. Instead, says Denis Duboule of the University of Geneva in Switzerland, minor variations in the amount of protein present might trigger development of particular tissues. That could be true for other gene families as well, says Duboule. "A lot of things we attribute to a particular quality of protein may be due instead to quantities," he says.