Outgrowth of the limb along the proximodistal axis depends on functions of the apical ectodermal ridge (AER), a specialized epithelial structure induced at the interface of dorsal and ventral ectodermal domains through a complex

Development of the vertebrate limb is an important paradigm for studying the regulation of growth and patterning in three dimensions, and both classical experiments and recent molecular approaches have provided significant insights into the mechanisms involved. These studies have revealed that growth and patterning along the three orthogonal axes (anteroposterior, dorsoventral, and proximodistal) of the limb are regulated by distinct but interdependent pathways, many aspects of which have been evolutionarily conserved (for reviews, see Johnson and Tabin, 1997; Martin, 1998; Schwabe et al., 1998; Vogt and Duboule, 1999). Limb bud formation is initiated by interaction of a specific region of lateral plate mesoderm, the limb field, with the overlying flank ectoderm. Dorsoventral polarity of the limb is controlled by the ectoderm (MacCabe et al., 1974), in part through secretion of WNT7A by the dorsal ectoderm, which activates the mesodermal target gene Lmx1 (Parr and McMahon, 1995; Riddle et al., 1995; Vogel et al., 1995). Outgrowth of the limb along the proximodistal axis depends on functions of the apical ectodermal ridge (AER), a specialized epithelial structure induced at the interface of dorsal and ventral ectodermal domains through a complex series of interactions (reviewed by Irvine and Vogt, 1997). Limb skeletal elements are laid down in a proximal to distal sequence, and predictable distal truncations result from removal of the AER (Saunders, 1948; Summerbell, 1974; Rowe and Fallon, 1982), which can be rescued by local application of FGFs that are expressed in the AER (Niswander et al., 1993; Fallon et al., 1994; Vogel et al., 1996). In contrast to the dorsoventral axis, anteroposterior polarity is an inherent property of the limb field mesoderm rather than the overlying ectoderm (Harrison, 1918; Hamburger, 1938; Zwilling, 1956; reviewed by Saunders, 1977). A key role in anteroposterior patterning of the limb is played by the zone of polarizing activity (ZPA), a region of mesoderm along the posterior margin of the limb bud that can direct growth and patterning when transplanted to the anterior side of a recipient limb bud, giving rise to mirror-image duplications of skeletal elements (Saunders and Gasseling, 1968). The secreted signaling molecule Sonic hedgehog (SHH) colocalizes with the ZPA and is sufficient to mimic its functions when ectopically expressed (Riddle et al., 1993). Maintenance of Shh expression depends on WNT7A signaling by dorsal ectoderm (Parr and McMahon, 1995; Yang and Niswander, 1995), and on FGF signaling by the AER (Laufer et al., 1994; Niswander et al., 1994). Conversely, maintenance of the AER depends on 2461 Development 127, 2461-2470 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 DEV3210