The Zone of Polarizing Activity (ZPA) is an area of mesenchyme that contains signals which instruct the developing limb bud to form along the anterior/posterior axis. Limb bud is undifferentiated mesenchyme enclosed by an ectoderm covering. Eventually, the limb bud develops into bones, tendons, muscles and joints. Limb bud development relies not only on the zone of polarizing activity, but also many different genes, signals, and a unique region of ectoderm called the apical ectodermal ridge (AER). Research by Saunders and Gasseling in 1948 identified the AER and its subsequent involvement in proximal distal outgrowth. Twenty years later, the same group did transplantation studies in chick limb bud and identified the ZPA. It wasn’t until 1987 that Todt and Fallon showed that the AER and ZPA are dependent on each other.
Patterning along the limb bud requires signals from many sources. Specifically, proteins called transcription factors (TF) help control the rate at which a gene is transcribed. The limb bud expresses a TF called ALX4 at the anterior part of the mesoderm, with the TF HOXB8 being expressed at the posterior portion. The Alx4 region, the medial region, and the Hox8 expressing area meet at a proximal area where the AER develops. The ZPA forms where the Hox8 region joins the AER.