The limb bud remains active throughout much of limb development as it stimulates the creation and positive feedback retention of two signaling regions: the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) with the mesenchymal cells. These signaling centers are crucial to the proper formation of a limb that is correctly oriented with its corresponding axial polarity in the developing organism. Research has determined that the AER signaling region within the limb bud determines the proximal-distal axis formation of the limb using FGF signals. ZPA signaling establishes the anterior-posterior axis formation of the limb using Shh signals. Additionally, though not known as a specific signaling region like AER and ZPA, the dorsal-ventral axis is established in the limb bud by the competitive Wnt7a and BMP signals that the dorsal ectoderm and ventral ectoderm use respectively. Because all of these signaling systems reciprocally sustain each other’s activity, limb development is essentially autonomous after these signaling regions have been established.