SONIC HEDGEHOG DIFFERENTIALLY REGULATES EXPRESSION OF GLI AND GLI3 DURING LIMB DEVELOPMENT

Sonic hedgehog is a secreted factor regulating patterning of the anter ior-posterior axis in the developing limb. The signaling pathway media ting the transduction of the signal is still poorly understood. In Dro sophila several genes are known to act downstream of hedgehog, the ny homolog of Sonic hedgehog. An important gene epistatic to hedgehog is cubitus interruptus, which encodes the by homolog of a family of verte brate putative transcription factors, the GLI genes. We have isolated two members of the GLI family from chick, called GLI and GL13. Their e xpression patterns in a variety of tissues during embryogenesis sugges t that these genes may be targets of the Sonic hedgehog signal. We dem onstrate that the two GLI genes are differentially regulated by Sonic hedgehog during limb development. Sonic hedgehog up-regulates GLI tran scription, while down-regulating GLI3 expression in the mesenchymal ce lls of the developing limb bud. Finally, we demonstrate that an activa ted form of GLI can induce expression of Patched, a known target of So nic hedgehog, thus implicating GLI as a key transcription factor in th e vertebrate hedgehog signaling pathway. In conjunction with evidence from a mouse Gli3 mutant, our data suggest that GLI and GLI3 may have taken two different functions of their Drosophila homolog cubitus inte rruptus. (C) 1996 Academic Press, Inc.