Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb

Ci/Gli zinc finger proteins mediate the transcriptional effects of Hedgehog protein signals. In Drosophila, Ci action as transcriptional repressor or activator is contingent upon Hedgehog-regulated, PKA-dependent proteolytic processing. We demonstrate that PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner anta gonized by apparent long-range signaling from posteriorly localized Sonic h edgehog protein. The resulting anterior/posterior Gli3 repressor gradient c an be perturbed by mutations of Gli3 in human genetic syndromes or by misre gulation of Gli3 processing in the chicken mutant talpid(2), producing a ra nge of limb patterning malformations. The high relative abundance and poten cy of Gli3 repressor suggest specialization of Gli3 and its products for ne gative Hedgehog pathway regulation.