Secreted sonic hedgehog (Shh) signals control digit number and identity in the developing vertebrate limb. However, the molecular mechanisms that make thumbs and `pinkies' look different are unclear. On , Chen et al. report how Gli3 and the Hoxd proteins (both have been previously implicated in digit development) might be involved in this process, with their finding that digit pattern is partly regulated by a varying ratio of Gli3 to total Hoxd protein across the mouse limb bud. Gli3, the intracellular mediator of Shh,exists in an activator form and a truncated repressor form that shuts off Shh target gene expression. The researchers identify a genetic and physical interaction between Gli3 and Hoxd12 (a 5′Hoxd member) that converts the Gli3 repressor into an activator of Shh targets. Other 5′Hoxd genes are also expressed differentially across the limb bud. These findings therefore highlight how the Hoxd proteins might function quantitatively to regulate digit pattern and identity.
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