Anterior to posterior patterning in the limb bud is determined by the zone of polarizing activity (ZPA). It is a small area of mesoderm that resides at the posterior margin of the apical ectodermal ridge (AER) where the limb bud meets the body wall. The ZPA produces a protein which has a concentration gradient from posterior to anterior, as predicted by the diffusable morphogen model suggested by Wolpert: the closer the limb bud cells are to the molecule, the more ulnar the structure that will be formed.
This is borne out by a number of animal studies. Transplantion of the ZPA to the opposite side of the limb bud produces a mirror limb - duplication along the radioulnar axis. Equally, insertion of a non-permeable barrier half way across the limb bud prevents the differentiation of anterior structures. Retinoic acid (RA)-soaked beads can mimic the effect of the ZPA in a dose-dependent manner.
It is thought that the protein product of the gene sonic hedgehog (Shh) is intimately involved in AP patterning. Application of exogenous Shh gene product to the anterior limb limb bud results in duplication, mimicking the effect of the ZPA. RA is known to induce Shh activity. Shh may activate the gene BMP-2 downstream which in turn may determine Hox gene expression and AP patterning. BMP-2 also has an effect on the morphogen FGF-4 from the apical ectodermal ridge (AER), so facilitating interaction between the processes causing proximo-distal and antero-posterior patterning.
The AER has a role in maintaining the ZPA. Removing the AER reduces Shh expression whereas adding FGF increases expression.
Abnormalities of AP patterning result in longitudinal disorders of differentiation such as syndactyly and polydactyly.
Ref: Wolpert L. J Theor Biol (1969); 25(1): 1-47.
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