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

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Abstract
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.