Vertebrate limb development and malformations.

To understand limb abnormalities it is necessary to understand how the limb develops. The limb is the organ whose development is probably best understood. The limbs develop from small protrusions (the limb buds) that arise from the body wall of the embryo. Positioning and patterning the limb involves cellular interactions both between the ectoderm surrounding the limb bud and between the mesenchymal cells that form the core of the limb bud. As the limb grows out the cells acquire a positional value that relates to their position in the bud with respect to all three axes, proximo-distal, antero-posterior, and dorso-ventral. These positional values largely determine how the cells will develop such as what sort of cartilaginous elements they will form. The positional value of the cells is acquired in the progress zone at the tip of the growing bud. The time spent in the progress zone may determine the positional values along the proximo-distal axis, that is the formation of, for example the humerus, then the radius and ulna. Loss of the progress zone due to damage to the overlying apical ridge leads to truncations, and this progress zone model can also account for the effects of thalidomide. Position along the antero-posterior axis such as the character of the digits is by a signal from the polarizing region at the posterior margin of the limb and involves the signaling protein Sonic hedgehog. A signal from the dorsal ectoderm specifies the dorso-ventral axis. Hox genes that are transcription factors are expressed both along the body axis and in a complex pattern in the limb and may record positional value. Human mutations in these genes lead to limb abnormalities. Muscle cells have a separate origin from the cartilaginous cells and those that form connective tissue and tendons, and they migrate into the bud from the somites and are patterned by the connective tissue. Cell death separates the digits.