1. Department of Zoology and Animal Biology and National Research Centre 'Frontiers in Genetics', University of Geneva, Sciences III, Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland
2. Present addresses: Department of Biology, McGill University, 1205 Avenue Docteur Penfield, Montreal H3A 1B1, Quebec, Canada (B.T.); Laboratory of Genetics and Development, Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal, 110 avenue des Pins Ouest, H2W 1R7, Montréal, Quebec, Canada (M.K.)

Correspondence to: Denis Duboule¹ Correspondence and requests for materials should be addressed to D.D. (Email: denis.duboule@zoo.unige.ch).

Abstract

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 buds^{1, 2}, under the control of HOX proteins encoded by gene members of both the HoxA and HoxD clusters^{3, 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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