Defect in the maintenance of the apical ectodermal ridge in the Dactylaplasia mouse

During vertebrate limb development the distal apex of the limb bud ectoderm is induced to form the apical ectodermal ridge (AER). The presence of the AER is required for the continued outgrowth of the limb bud. Classical embryological studies have led to the hypothesis that a secreted mesenchymal factor is required to maintain the AER. We have undertaken a detailed analysis of Dactylaplasia (Dac) mice, a semidominant mutant which displays missing central digits in the fore- and hindlimbs of heterozygous animals and monodactyly in homozygous animals. Our data show that Dac mice have a defect in the maintenance of the AER. At E10.5, the mutant AER is found to be morphologically normal. However, by E11.5 the central aspect of the AER degenerates leaving the anterior and posterior AER intact. In homozygous mice both the central and anterior AER degenerate, while the posterior extremity of the AER is unaffected. Analysis of BrdU incorporation reveals that degeneration of the AER is due to a lack of cell proliferation in the mutant AER. The loss of the AER leads to a reduction in cell proliferation in the subridge mesenchyme at E11.5. The data represent direct genetic evidence for the existence of an AER maintenance activity that is distinct from AER induction and differentiation. Moreover, the data suggest that the role of the AER maintenance factor is to promote cell proliferation in the ridge. Based on our findings, we propose a model for AER maintenance in the vertebrate limb.