Crackower M A, Motoyama J, Tsui L C
Department of Molecular and Medical Genetics, University of Toronto, Toronto, Canada.
Dev Biol. 1998 Sep 1;201(1):78-89. doi: 10.1006/dbio.1998.8938.
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.
在脊椎动物肢体发育过程中，肢芽外胚层的远端顶端被诱导形成顶端外胚层嵴（AER）。肢体芽的持续生长需要AER的存在。经典胚胎学研究提出了一种假说，即需要一种分泌的间充质因子来维持AER。我们对多指（趾）畸形（Dac）小鼠进行了详细分析，Dac小鼠是一种半显性突变体，杂合动物的前肢和后肢中缺少中央指（趾），纯合动物表现为单指（趾）畸形。我们的数据表明，Dac小鼠在维持AER方面存在缺陷。在胚胎第10.5天（E10.5），突变体的AER在形态上是正常的。然而，到E11.5时，AER的中央部分退化，而AER的前部和后部保持完整。在纯合小鼠中，AER的中央和前部都退化，而AER的后部不受影响。对5-溴脱氧尿嘧啶核苷（BrdU）掺入的分析表明，AER的退化是由于突变体AER中细胞增殖不足所致。AER的缺失导致E11.5时嵴下间充质中细胞增殖减少。这些数据代表了一种与AER诱导和分化不同的AER维持活性存在的直接遗传学证据。此外，数据表明AER维持因子的作用是促进嵴中的细胞增殖。基于我们的发现，我们提出了一个脊椎动物肢体中AER维持的模型。
