SPECIFIC AND REDUNDANT FUNCTIONS OF GLI2 AND GLI3 ZINC-FINGER GENES IN SKELETAL PATTERNING AND DEVELOPMENT

The correct patterning of vertebrate skeletal elements is controlled b y inductive interactions. Two vertebrate hedgehog proteins, Sonic hedg ehog and Indian hedgehog, have been implicated in skeletal development . During somite differentiation and limb development, Sonic hedgehog f unctions as an inductive signal from the notochord, floor plate and zo ne of polarizing activity. Later in skeletogenesis, Indian hedgehog fu nctions as a regulator of chondrogenesis during endochondral ossificat ion. The vertebrate Gli zinc finger proteins are putative transcriptio n factors that respond to Hedgehog signaling. In Drosophila, the Gli h omolog cubitus interruptus is required for the activation of hedgehog targets and also functions as a repressor of hedgehog expression. We s how here that Gli2 mutant mice exhibit severe skeletal abnormalities i ncluding cleft palate, tooth defects, absence of vertebral body and in tervertebral discs, and shortened limbs and sternum. Interestingly, Gl i2 and Gli3 (C.-c. Hui and A. L. Joyner (1993). Nature Genet. 3, 241-2 46) mutant mice exhibit different subsets of skeletal defects indicati ng that they implement specific functions in the development of the ne ural crest, somite and lateral plate mesoderm derivatives. Although Gl i2 and Gli3 are not functionally equivalent, double mutant analysis in dicates that, in addition to their specific roles, they also serve red undant functions during skeletal development. The role of Gli2 and Gli 3 in Hedgehog signaling during skeletal development is discussed.