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 underst ood. The limbs develop from small protrusions (the Limb buds) that arise fr om the body wall of the embryo. Positioning and patterning the limb involve s cellular interactions both between the ectoderm surrounding the limb bud and between the mesenchymal cells that form the core of the limb bud. As th e 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 ho w the cells will develop such as what sort of cartilaginous elements they H ill form. The positional value of the cells is acquired in the progress zon e at the tip of the growing bud. The time: spent in the progress zone may d etermine the positional values along the proximo-distal axis, that is the f ormation 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 truncat ions, and this progress zone model can also account for the effects of thal idomide. Position along the antero-posterior axis such as the character of the digits is by a signal from the polarizing region at the posterior margi n of the Limb and involves the signaling protein Sonic hedgehog. A signal f rom the dorsal ectoderm specifies the dorso-ventral axis. Hox genes that ar e transcription factors are expressed both along the body axis and in a com plex pattern in the limb and may record positional value. Human mutations i n these genes lead to limb abnormalities. Muscle cells have a separate orig in from the cartilaginous cells and those that form connective tissue and t endons, and they migrate into the bud from the somites and are patterned by the connective tissue. Cell death separates the digits.