Limb development and thalidomide-induced phocomelia. (a) Normal limb development. The limb grows out from the embryonic flank under the control of several signalling regions, the Zone of Polarising Activity (ZPA) and the Apical Ectodermal Ridge (AER). These signalling regions release signalling molecules Shh and Fgf8, respectively, which signal in a feedback loop and control limb outgrowth and patterning. Ultimately other genes are activated including Hox genes, which are involved in patterning the fine detail of the cartilage elements [51, 52]. (b) Model of thalidomide-induced phocomelia. Thalidomide inhibits blood vessel formation and migration, resulting in cell death and reduced signalling between the ZPA and AER. Once thalidomide exposure has ceased or limb has recovered, AER/ZPA signalling could be reestablished and remaining cells distalised to produce a phocomelic limb. If thalidomide exposure was long term, AER/ZPA signalling may be completely abolished, resulting in Amelia.
