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Limb anomalies are important birth defects that are incompletely understood genetically and mechanistically.  GLI3 , a mediator of hedgehog signaling, is a genetic cause of limb malformations including pre- and postaxial polydactyly, Pallister–Hall syndrome and Greig cephalopolysyndactyly. A closely related Gli (glioma-associated oncogene homolog)-superfamily member,  ZIC3 , causes X-linked heterotaxy syndrome in humans but has not been investigated in limb development. During limb development, post-translational processing of Gli3 from activator to repressor antagonizes and posteriorly restricts Sonic hedgehog (Shh). We demonstrate that  Zic3  and  Gli3  expression overlap in developing limbs and that Zic3 converts Gli3 from repressor to activator  in vitro . In  Gli3  mutant mice,  Zic3  loss of function abrogates ectopic  Shh  expression in anterior limb buds, limits overexpression in the zone of polarizing activity and normalizes aberrant Gli3 repressor/Gli3 activator ratios observed in  Gli3 +/− embryos.  Zic3  null; Gli3 +/− neonates show rescue of the polydactylous phenotype seen in  Gli3 +/− animals. These studies identify a previously unrecognized role for Zic3 in regulating limb digit number via its modifying effect on  Gli3  and  Shh  expression levels. Together, these results indicate that two Gli superfamily members that cause disparate human congenital malformation syndromes interact genetically and demonstrate the importance of Zic3 in regulating Shh pathway in developing limbs.

Preaxial polydactyly caused by Gli3 haploinsufficiency is rescued by Zic3 loss of function in mice