A Switch Between Topological Domains Underlies HoxD Genes Collinearity in Mouse Limbs

Guillaume Andrey, Thomas Montavon, Bénédicte Mascrez, Federico Gonzalez, Daan Noordermeer, Marion Leleu, Didier Trono, François Spitz, Denis Duboule

Science 7 June 2013: Vol. 340 no. 6137 dpi: 10.1126/science.1234167

Editors Summary

During limb development, the time and place of Hox transcription are fixed by respective gene position within the gene cluster. Andrey et al. (p. 1234167; see the Perspective by Rodrigues and Tabin) found that this enigmatic property results from the opposite and successive actions of two large regulatory landscapes located on either side of the mouse Hox locus. In the early phase, one of these topological domains regulates transcription in the proximal limb until a switch occurs toward the other topological domain, which takes over the regulation in the distally developing digits. As a side effect of this antagonistic regulatory strategy, cells in-between have lessened Hox transcription, which generates the wrist.

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Hox genes are major determinants of the animal body plan, where they organize structures along both the trunk and appendicular axes. During mouse limb development, Hoxd genes are transcribed in two waves: early on, when the arm and forearm are specified, and later, when digits form. The transition between early and late regulations involves a functional switch between two opposite topological domains. This switch is reflected by a subset of Hoxd genes mapping centrally into the cluster, which initially interact with the telomeric domain and subsequently swing toward the centromeric domain, where they establish new contacts. This transition between independent regulatory landscapes illustrates both the modularity of the limbs and the distinct evolutionary histories of its various pieces. It also allows the formation of an intermediate area of low HOX proteins content, which develops into the wrist, the transition between our arms and our hands. This regulatory strategy accounts for collinear Hox gene regulation in land vertebrate appendages.

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