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Regulatory constraints in the evolution of the tetrapod limb anterior–posterior polarity


The anterior to posterior (A–P) polarity of the tetrapod limb is determined by the confined expression of Sonic hedgehog (Shh) at the posterior margin of developing early limb buds1,2, under the control of HOX proteins encoded by gene members of both the HoxA and HoxD clusters3,4,5,6. Here, we use a set of partial deletions to show that only the last four Hox paralogy groups can elicit this response: that is, precisely those genes whose expression is excluded from most anterior limb bud cells owing to their collinear transcriptional activation. We propose that the limb A–P polarity is produced as a collateral effect of Hox gene collinearity, a process highly constrained by its crucial importance during trunk development. In this view, the co-option of the trunk collinear mechanism, along with the emergence of limbs, imposed an A–P polarity to these structures as the most parsimonious solution. This in turn further contributed to stabilize the architecture and operational mode of this genetic system.

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Figure 1: Control of Shh expression by Hoxa and Hoxd genes.
Figure 2: 5′-located Hox genes induce Shh expression in a gene-specific and dose-dependent manner.
Figure 3: Skeletons of the various mutant stocks in either the presence (top) or absence (bottom) of Shh signalling.
Figure 4: Regulatory constraints in the emergence of the limb A–P polarity.


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We thank N. Fraudeau and T. H. N. Huynh for technical assistance as well as C. Tabin and M. Coates for comments and suggestions. This work was supported by funds from the canton de Genève, the Louis-Jeantet foundation, the Swiss National Research Fund, the National Center for Competence in Research (NCCR) ‘Frontiers in Genetics’ and the EU programme ‘Cells into Organs’.

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Correspondence to Denis Duboule.

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Tarchini, B., Duboule, D. & Kmita, M. Regulatory constraints in the evolution of the tetrapod limb anterior–posterior polarity. Nature 443, 985–988 (2006).

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