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Serial deletions and duplications suggest a mechanism for the collinearity of Hoxd genes in limbs


Hox genes, located at one end of the HoxD cluster, are essential for the development of the extremities of our limbs; that is, the digits. This ‘collinear’ correspondence is accompanied by a gradual decrease in the transcriptional efficiency of the genes. To decipher the underlying regulatory mechanisms, and thus to understand better how digits develop, we engineered a series of deletions and duplications in vivo. We find that HoxD genes compete for a remote enhancer that recognizes the locus in a polar fashion, with a preference for the 5′ extremity. Modifications in either the number or topography of Hoxd loci induced regulatory reallocations affecting both the number and morphology of digits. These results demonstrate why genes located at the extremity of the cluster are expressed at the distal end of the limbs, following a gradual reduction in transcriptional efficiency, and thus highlight the mechanistic nature of collinearity in limbs.

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We thank M. Friedli for technical assistance, and J. Zakany and other colleagues from the Duboule laboratory for sharing mice, reagents, discussions and comments on the manuscript. This work was supported by funds from the Canton de Genève, the Swiss National Research Fund, the Claraz, Latsis, Cloetta and Louis-Jeantet foundations, as well as the NCCR Frontiers in Genetics.

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Correspondence to Denis Duboule.

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The authors declare that they have no competing financial interests.

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Supplementary Figure 1 (JPG 208 kb)

Supplementary Figure 2 (JPG 161 kb)

Supplementary Figure Legends and Table 3 (DOC 29 kb)

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Further reading

Figure 1: Collinearity in developing limbs.
Figure 2: Targeted deletions induce regulatory reallocations.
Figure 3: The evolutionarily conserved region RXII cooperates with the Hoxd13 locus for positioning the enhancer in the 5′ end of the cluster.
Figure 4: Supernumerary loci titrate the effect of the digit enhancer in a polar fashion.
Figure 5: Impact of Hoxd loci deletions and duplications on the regulation of Evx2.
Figure 6: A potential mechanism underlying collinearity in limbs.


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