Antagonists Go out on a Limb

based on antagonistic interactions that suggests how Princeton University in the vertebrate limb proximal–distal specification is Princeton, New Jersey 08544 coordinated with the control of limb bud outgrowth and Quai Ernest-Ansermet 30 Both invertebrates and vertebrates employ homeotic 1211 Geneva 4 genes to produce segmental diversity along the main Switzerland body axis. These genes also play critical roles in the development of appendages, including the determination of limb position along the body axis, cell fate deter-Animal appendages exhibit a spectacular diversity of mination in the limb bud, and the control of cell prolifera-forms related to function and lifestyle. As revealed in tion and thereby the extent of proximal-distal outgrowth. studies ranging from Drosophila to man, appendages Hox proteins function as transcription factors and their as evolutionary innovations have recruited many of the activities are regulated by association with cofactors genetic pathways involved in patterning the major body such as those encoded by the Drosophila extradenticle axis. During Drosophila larval development, wings and legs arise from distinct sheets of epithelial cells called imaginal discs (Figures 1A–1C). The leg disc is patterned by the expression of hedgehog (hh) in the posterior compartment , which leads to induction of two signaling pathways , decapentaplegic (dpp) in dorsal cells and wing-less (wg) in ventral cells (for review see Brook et al., 1996). Together, these two morphogens serve to induce a distal program of genes promoting outgrowth along the proximal–distal (PD) axis, while acting antagonistically to pattern along the dorsal-ventral (DV) axis (Figure 1B). The most distal elements (claws) of Drosophila legs derive from the center of the disc as the final structure emerges in a telescoping fashion during metamorphosis (Figure 1C). Development of the vertebrate limb involves somewhat different processes and relies upon interactions between two tissues (Figures 1D–1F). The limb first appears as a bud of mesoderm cells originating in the lateral plate mesoderm, covered by surface ectoderm. Growth and patterning is dependent on an epithelial– mesenchymal interaction that occurs between a distal organizing center, the apical ectodermal ridge (AER), which is formed at the dorsal–ventral interface of the epithelium, and the underlying mesenchyme (progress zone); proliferation of the progress zone mesenchyme is prompted by the Fgf produced in the AER, and in turn, factors produced by the progress zone maintain the AER (Figure 1B; for review see Martin, 1998). Em-bryological studies of this interaction in chick limb buds demonstrated that proximal structures …