Dorsalizing signal Wnt-7a required for normal polarity of D-V and A-P axes of mouse limb.

Formation of the vertebrate limb requires specification of cell position along three axes. Proximal-distal identity is regulated by the apical ectodermal ridge (AER) at the distal tip of the growing limb. Anterior-posterior identity is controlled by signals from the zone of polarizing activity (ZPA) within the posterior limb mesenchyme. Dorsal-ventral identity is regulated by ectodermally derived signals. Recent studies have begun to identify signalling molecules that may mediate these patterning activities. Members of the fibroblast growth factor (FGF) family are expressed in the AER and can mimic its proximal-distal signalling activity. Similarly, the gene Sonic hedgehog (Shh) is expressed in the ZPA, and Shh-expressing cells, like ZPA cells, can cause digit duplications when transplanted to the anterior limb margin. In contrast, no signal has yet been identified for the dorsal-ventral axis, although Wnt-7a is expressed in the dorsal ectoderm, suggesting that it may play such a role. To test this possibility, we have generated mice lacking Wnt-7a activity. The limb mesoderm of these mice shows dorsal-to-ventral transformations of cell fate, indicating that Wnt-7a is a dorsalizing signal. Many mutant mice also lack posterior digits, demonstrating that Wnt-7a is also required for anterior-posterior patterning. We propose that normal limb development requires interactions between the signalling systems for these two axes.