Rethinking the proximodistal axis of the vertebrate limb in the molecular era

The development of the vertebrate limb has long served as a paradigm for understanding the fundamental processes by which an undifferentiated field of cells gains spatial pattern and undergoes coordinated differentiation to produce the exquisitely complex structures that characterize our functional anatomy. The limb bud emerges from the flank as a mound of seemingly homogeneous mesenchymal cells within an ectodermal jacket. Yet within days this mass of cells gives rise to skeletal elements, muscles, and connective tissues organized in the form of a mature limb. Looking at one’s own arm or leg, this organization can immediately be appreciated along three different axes: The back of the hand (dorsal) is different from the palm (ventral), the thumb (anterior) is distinct from the little finger (posterior), and the upper arm (proximal) is different from the lower arm and the hand (distal). The process by which differences along the proximodistal axis are established has been particularly controversial, with competing models proposed to explain the outcome of both classical and genetic manipulations. However, if one examines the two major models that have been previously proposed, neither of them is tenable in the context of our current knowledge of gene activity in the developing limb. Proximodistal patterning therefore needs to be placed into a new framework based directly on the molecular data.

The first key insight into the process of limb patterning came almost 60 yr ago when John Saunders discovered that the apical ectodermal ridge (AER), a thickened ridge of ectodermal cells that runs along the anterior–posterior axis of the distal limb bud (equivalent to a ridge running along the distal edge of the hand from which the finger tips will eventually form) is necessary for the successful outgrowth of the limb along the proximodistal axis (Saunders 1948). To explain how different structures arise …