Hox dosage and morphological diversification during development and evolution

Hox genes encode for evolutionary conserved transcription factors that have long fascinated biologists since the observation of the first homeotic transformations in flies. Hox genes are developmental architects that instruct the formation of various and precise morphologies along the body axes in cnidarian and bilaterian species. In contrast to these highly specific developmental functions, Hox genes encode for proteins that display poorly selective DNA-binding properties in vitro. This "Hox paradox" has been partially solved with the discovery of the TALE-class cofactors, which interact with all Hox members and form versatile Hox/TALE protein complexes on DNA. Here, we describe the role of the Hox dosage as an additional molecular strategy contributing to further resolve the Hox paradox. We present several cases where the Hox dosage is involved in the formation of different morphologies in invertebrates and vertebrates, with a particular emphasis on flight appendages in insects. We also discuss how the Hox dosage could be interpreted in different types of target enhancers within the nuclear environment in vivo. Altogether our survey underlines the Hox dosage as a key mechanism for shaping Hox molecular function during development and evolution.