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The vertebrate limb is a complex organ with its components asymmetrically arranged along three main axes: proximal/distal, anterior/posterior, dorsal/ventral. The positions of each of the bones and muscles in the limb are precisely organized.
The skeletons of most vertebrate limbs develop as a series of precartilage primordia in a proximodistal (PD) fashion; the cartilaginous elements destined to be closest to the body form first, followed, successively by structures more and more distant from the body. The limb buds of vertebrates protrude from the body wall, or flank, at four discrete sites: two at the forelimbs and two at the hindlimbs. Limb bud formation is initiated in the embryo by the continued local proliferation of lateral plate mesodermal cells at the relevant axial levels, at a time of cessation of rapid growth of cells of the rest of the flank. The paddle-shaped limb bud, which gives rise to the skeleton and muscles, is surrounded by the ectoderm, a layer of simple epithelium. These proliferating mesenchymal cells form a bulge under the ectoderm. In avian and mammalian limb buds, the rapidly dividing mesodermal cells induce the ectodermal cells along the anterior to posterior rim of the bud, to elongate and form a specialized structure called the apical ectodermal ridge (AER). Once the AER has formed, it is responsible for maintaining the continued outgrowth of the limb bud and for patterning along the proximal-distal axis. In addition to initiating limb outgrowth, the presumptive limb mesoderm carries essential information for establishing anterior-posterior polarity of the limb. The zone of polarizing activity (ZPA), a specialized region at the posterior margin of the developing limb bud, is believed to be responsible for the normal patterning along the anterior- posterior axis of the limb bud. Interactions between the AER and the ZPA are critical for coordinating patterning and growth during limb development.
In week 4 after human fertilization (equivalent to mouse E9.0), the upper limb buds appear as small elevations at the sides of the trunk. About 2 days later, the lower limb buds appear. At this point, a mesenchymal skeleton exists in the limb buds; the masses of mesoderm surrounding the developing bones, which will become the skeletal muscles of the limbs, have migrated into the limbs from the myotome of the somite. By week 6, the limb buds develop a constriction around its middle portion. The constriction produces flattened distal segments of the upper buds, called hand plates, and distal segments of the lower buds, called foot plates. These plates represent the beginnings of the hands and feet, respectively. A cartilaginous skeleton is present at this stage. By week 7, the arm, forearm, and hand are evident in the upper limb bud, and the thigh, leg, and foot appear in the lower limb bud. By week 8, the shoulder, elbow, and wrist areas become apparent. Endochondral ossification of the limb bones begins by the end of week 8 (equivalent to E15.0 in mouse), and the digits are distinct and no longer webbed due to apoptosis of the cells of this region. By week 12, primary ossification centers are present in most of the limb bones. Most secondary ossification centers appear after birth.