Do 5'Hoxd genes play a role in initiating or maintaining A-P polarizing signals in the limb?

The analysis of multiple null mutants generated through targeted disruption indicates that the 5' members of the Hoxd and Hoxa clusters determine the skeletal pattern in the limb by regulating the formation and growth of the different chondrogenic precursors for the skeletal elements. While these studies have established that together these genes are the major players in regulating formation of the limb skeleton, the roles of individual members have often been difficult to evaluate fully due to extensive functional overlap between various 5'Hoxd and 5'Hoxa genes. The analysis of gain-of-function mutants provides a complementary approach to elucidate gene function in the presence of multiple redundancies. This approach has recently revealed that Hoxd-12 can induce Sonic hedgehog and suggests a new role for certain 5'Hoxd genes in the initiation of Sonic hedgehog expression and its maintenance through feedback regulation. Thus, some 5'Hoxd genes may be a part of the regulatory network that positions and reinforces polarizing signals in the posterior-distal limb bud.