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Presenting Author(s) Marie Kmita
Abstract Title A conditional loss-of-function strategy to assess the overall contribution of Hox genes to limb development.
Full author List Kmita M., Zàkàny J., Logan M., Tabin C.J., and D. Duboule
Text of abstract

Genes from the HoxA and HoxD clusters are known to be involved in the patterning process of the Vertebrate limbs. To understand the functional contribution of this gene family, a number of loss-of-function mutants have been produced and analysed. However, synergy, as well as redundancy and compensation between Hox products made difficult the assessment of the overall Hox functional input to limb morphogenesis. Because a global Hox inactivation was impossible due to the lethality associated to Hoxa13 inactivation, we undertook the analysis of limb morphogenesis in the absence of Hoxa and Hoxd genes using a conditional approach. We generated mice in which a loxP site was targeted at each extremity of the HoxA cluster and used the Prx1-Cre deleter strain to induce a tissue specific deletion. This conditional HoxA deletion was further combined with a full defiency of the HoxD cluster.

Double homozygous mice had dramatically truncated limbs with only a short humerus-like bone. Limb buds of corresponding embryos were reduced in size, suggesting a growth defect. Throughout development, the buds contained almost exclusively homothorax/Meis1 expressing cells, indicating that the mutant humerus-like bone derived from these cells. In addition, mutant buds were deprived of Shh transcripts, the molecular mediator of the ZPA, required for the anterior-posterior patterning process of the intermediate and distal part of the limb. While the late phase of Hox expression was previously shown to rely on Shh function, we show here that Shh transcription is dependent on Hoxa/Hoxd gene. Together these results demonstrate the absolute requirement of Hoxa and Hoxd genes for the morphogenesis of the Vertebrate limbs, in part through the activation of Shh transcription, and suggest a key role of the Hox genes in the emergence of the vertebrate distal limb.

Which session is your work most relevant to: "Limb patterning" (or possibly "Limb evolution")