Vertebrate limb development: from Harrison's limb disk transplantations to targeted disruption of Hox genes

Various animal organs have long been used to investigate the cellular and molecular nature of embryonic growth and morphogenesis. Among those organs, the tetrapod limb has been preferentially used as a model system for elucidating general patterning mechanisms. At the appropriate time during the embryonic period, the limb territories are first determined at the right positions along the cephalocaudal axis of the animal body, and soon the limb buds grow out from the flanks as mesenchymal cell masses covered by simple ectoderm. The position, number, and identity of the limbs depend on the expression of specific Hox genes. Limb morphogenesis occurs along three axes, which become gradually fixed: first the anteroposterior axis, then the dorsoventral, and finally the proximodistal axis, along which the bulk of limb growth occurs. Growth of the limb in amniotes depends on the formation of the apical ectodermal ridge, which, by secreting many members of the fibroblast growth factors family, attracts lateral plate and somitic mesodermal cells, keeps these cells in the progress zone proliferating, and prevents their differentiation until an appropriate time period. Mutual interactions between mesoderm and ectoderm are important in the growth process, and signaling regions have been identified, such as the zone of polarizing activity, the dorsal limb ectoderm, and the apical ectodermal ridge. Several molecules have been found to play leading roles in various biological processes relevant to morphogenesis. Besides its intrinsic merit as a model for unraveling the mechanisms of development, the limb deserves considerable clinical interest because defects of limb development are the most common single category of congenital abnormalities.