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Early developmental arrest of mammalian limbs lacking HoxA/HoxD gene function


Vertebrate HoxA and HoxD cluster genes are required for proper limb development1,2,3. However, early lethality, compensation and redundancy have made a full assessment of their function difficult3,4,5. Here we describe mice that are lacking all Hoxa and Hoxd functions in their forelimbs. We show that such limbs are arrested early in their developmental patterning and display severe truncations of distal elements, partly owing to the absence of Sonic hedgehog expression. These results indicate that the evolutionary recruitment of Hox gene function into growing appendages might have been crucial in implementing hedgehog signalling, subsequently leading to the distal extension of tetrapod appendages. Accordingly, these mutant limbs may be reminiscent of an ancestral trunk extension, related to that proposed for arthropods6.

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Figure 1: Conditional deletion of the HoxA cluster.
Figure 2: HoxA/HoxD double-mutant forelimbs.
Figure 3: Developmental arrest in forelimbs lacking Hox function.
Figure 4: Lack of Shh expression in double-mutant forelimbs.

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We thank A. McMahon, M. Torres, G. Martin, A. Ruiz I Altaba, C. Fromental-Ramain and E. Olson for probes, N. Fraudeau and M. Friedli for technical assistance, and J. Deschamps, G. Morata and P. Vassalli for discussions. This work was supported by funds from the canton de Genève, the Claraz and Louis Jeantet foundations, the Swiss National Research Fund, the NCCR ‘Frontiers in Genetics’ (to D.D.), a grant from the National Institutes of Health (to C.T.) and the EMBO young investigator program (to M.L.).

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Correspondence to Denis Duboule.

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Kmita, M., Tarchini, B., Zàkàny, J. et al. Early developmental arrest of mammalian limbs lacking HoxA/HoxD gene function. Nature 435, 1113–1116 (2005).

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