Hox gene expression in limbs: colinearity by opposite regulatory controls

Genes of the HoxD complex have a crucial role in the morphogenesis of vertebrate limbs. During development, their functional domains are colinear with their genomic positions within the HoxD cluster such that Hoxd13 and Hoxd12 are necessary for digit development, whereas Hoxd11 and Hoxd10 are involved in making forearms. Mutational analyses of these genes have demonstrated their importance and illustrated the requirement for a precise control of their expression during early limb morphogenesis. To study the nature of this control, we have scanned the posterior part of the HoxD complex with a targeted reporter transgene and analyzed the response of this foreign promoter to limb regulatory influences. The results suggest that this regulation is achieved through the opposite effects of two enhancer elements which would compete with each other for interacting with nearby-located promoters. The physical position of a given gene within this genomic interval of opposite regulations might thus determine its final expression pattern. This model provides a conceptual link between the morphology of the future limb and the genetic organization of the Hox gene cluster, a translation of a genomic context into a morphogenetic topology.