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Significance To understand the special morphology of the thumb (digit 1), an important adaptation of the human hand, we studiedHoxa13 -null mice that specifically lack this digit. We show thatHoxa13 mutant limbs specifically loseHoxd13 expression in the presumptive digit 1 region, correlating with increasedGli3 transcription and Gli3 repressor activity. We also show that Hox13 paralogs regulateGli3 transcription by negatively modulating the activity ofGli3 enhancers. Our results indicate that mutual antagonism between Gli3 and Hox13 paralogs determines the anterior−posterior asymmetry of the handplate and that Hoxa13 acts hierarchically to initiate formation of a digit 1 territory by attenuatingGli3 transcription and enabling second-phase expansion of5′Hoxd expression.

The formation of the thumb requires direct modulation of Gli3 transcription by Hoxa13