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

Nature volume 420, pages 145–150 (2002)Cite this article

Abstract

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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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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Acknowledgements

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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  1. Yann Hérault

    Present address: Molecular and Experimental Genetics, FRE2358, CNRS, Institut de Transgénose, rue de la Férollerie, 3B, 45071, Orléans, Cedex 2, France

Authors and Affiliations

  1. Department of Zoology and Animal Biology, NCCR Frontiers in Genetics, University of Geneva, Sciences III, Quai Ernest Ansermet 30, 1211 4, Geneva, Switzerland

    Marie Kmita, Nadine Fraudeau, Yann Hérault & Denis Duboule

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Correspondence to Denis Duboule.

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Kmita, M., Fraudeau, N., Hérault, Y. et al. Serial deletions and duplications suggest a mechanism for the collinearity of Hoxd genes in limbs. Nature 420, 145–150 (2002). https://doi.org/10.1038/nature01189

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