Hoxd genes are essential for limb growth and patterning. They are activated following a complex transcriptional regulation, leading to expression domains that are collinear in both space and time. To understand the mechanism(s) underlying collinearity, we produced and analyzed a set of mouse strains containing systematic deletions and duplications within the HoxD cluster. We show that two waves of transcriptional activation, controlled by different mechanisms, generate the observed developmental expression patterns. The first wave is time-dependent, involves the action of opposite regulatory modules, and is essential for the growth and polarity of the limb up to the forearm. The second phase involves a different regulation and is required for the morphogenesis of digits. We propose that these two phases reflect the different phylogenetic histories of proximal versus distal limb structures and discuss the biological relevance of these collinear patterns, particularly for the origin of the anterior-to-posterior limb polarity.
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