The apical ectodermal ridge (AER) is a structure that forms from the ectodermal cells at the distal end of each limb bud and acts as a major signaling center to ensure proper development of a limb. After the limb bud induces AER formation, the AER and limb mesenchyme—including the zone of polarizing activity (ZPA)—continue to communicate with each other to direct further limb development. The position of the limb bud, and hence the AER, is specified by the expression boundaries of Hox genes in the embryonic trunk. At these positions, the induction of cell outgrowth is thought to be mediated by a positive feedback loop of fibroblast growth factors (FGFs) between the intermediate mesoderm, the lateral plate mesoderm and the surface ectoderm. FGF8 in the intermediate mesoderm signals to the lateral mesoderm, restricting the expression of FGF10 through intermediate Wnt signals. Then, FGF10 in the lateral plate mesoderm signals to the surface ectoderm to create the AER, which expresses FGF8. The AER is known to express FGF2, FGF4, FGF8, and FGF9, while the limb bud mesenchyme expresses FGF2 and FGF10. Embryo manipulation experiments have shown that some of these FGFs alone are sufficient for mimicking the AER.