Molecular Models for Vertebrate Limb Development

Soon after the AER forms, mesenchy-mal cells aggregate to form cartilage blastemal elements M. D. Anderson Cancer Center Houston, Texas 77030 that prefigure skeletal limb components (Hall and Mi-yake, 1992). Cells directly under the AER remain undif-† Department of Genetics Harvard Medical School ferentiated in the so-called " progress zone, " while condensation initiates in proximal limb regions, so that the Boston, Massachusetts 02115 humeral analage forms first, followed by the radius and ulna, and lastly the digits. The net result of these developmental processes is the establishment of familiar pro-The three-dimensional form of organisms is achieved totypical tetrapod limb features (Figure 1C). The first through a process called pattern formation. For the clues to how this complex shape and form is achieved most part, general features of animal body plans are came from the work of experimental embryologists who initially laid out during embryogenesis in broad strokes. identified specific regions of the developing chick limb For instance, differential fates are specified along the bud that are essential in directing growth and patterning. rostral–caudal axis. During subsequent development, further refinement of these broad distinctions occurs, Fibroblast Growth Factors Specify the Limb leading to the formation of semi-autonomous regions, Field and Promote Initial Outgrowth commonly referred to as secondary fields, in which the A clue to how growth within the limb field may be regu-process of regional specification is repeated anew. Pat-lated came from foil barrier and extirpation studies, tern formation in secondary fields can be conceptual-which indicated that the intermediate mesoderm is re-ized as occurring in four stages: first, the cells that make quired for limb bud initiation (Stephens and McNulty, up the field itself are defined; second, specific signaling 1981; Strecker and Stephens, 1983; Geduspan and So-centers are established within the field, which serve lursh, 1992). Limbs will not form when a barrier is placed to provide positional information; third, this positional between lateral plate and intermediate mesoderm. Simi-information is recorded on a cell-by-cell basis; and fi-larly, removal of intermediate mesoderm results in loss nally, cells differentiate in response to additional cues of adjacent limb tissue. One interpretation of these ex-according to their already-encoded positional informa-periments is that the intermediate mesoderm produces tion. The molecular basis for these four events is the a factor that maintains proliferation of the flank in pre-subject of much current interest in developmental biol-sumptive limb regions. However, it should be noted that ogy, and …