ANTAGONISM BETWEEN EXTRADENTICLE FUNCTION AND HEDGEHOG SIGNALING IN THE DEVELOPING LIMB

The Drosophila homeobox gene extradenticle (exd) encodes a highly cons erved cofactor of Hox proteins(1-3). exd activity is regulated post-tr anslationally by a mechanism involving nuclear translocation(4,5); onl y nuclear Exd protein is functional. The exd gene is required for patt erning of the proximal region of the leg(6,7), whereas patterning of t he distal region requires signalling by the Wingless (Wg) and Decapent aplegic (Dpp)(8,9) proteins, which are in turn activated by Hedgehog ( Hh)(10). Here we show that exd function and Dpp/Wg signalling are anta gonistic and divide the leg into two mutually exclusive domains. In th e proximal domain, exd activity prevents cells from responding to Dpp and Wg, Conversely, in the distal domain, exd function is suppressed b y the Dpp/Wg response gene Distal-less (Dll), which prevents the nucle ar transport of Exd, We also found that the product of a murine homolo gue of exd (Pbx1) is regulated at the subcellular level, and that its pattern of nuclear localization in the mouse limb resembles that of Ex d in the Drosophila leg. These findings suggest that the division of t he limb into two antagonistic domains, as defined by exd (Pbx1) functi on and Hh signalling, may be a general feature of limb development.