Figure 3.

Embryonic limb development. Limbs form from a bud from the flanks of the embryo. In humans the upper limbs form around a day earlier (day 26) than the lower limbs (day 27). The limb bud consists of two key signaling centers. The apical ectodermal ridge (AER), a thickened epithelium lining the distal tip of the bud and separating the dorsal from ventral surface; and the zone of polarizing activity (ZPA) in the posterior‐distal mesenhcyme. The AER expresses Fgf8 which signals to the mesenchyme to induce Fgf10 and to the ZPA to induce and maintain Shh, which itself feeds back to maintain Fgf8. This feedback loop maintains cell proliferation and limb outgrowth and induces other genes, for example the Hox genes, which establish the pattern of the limb elements, humerus, radius, ulna, and handplate, as well as the soft tissues. The limbs grow out from specific regions of the flank of the embryo and as the limb grows out the limb is patterned proximally to distal, that is, humerus/femur are laid down before the radius, ulna/fibular, tibia, and then the handplate/footplate.