Mouse limbs expressing only the G1i3 repressor resemble those of Sonic hedgehog mutants
Mouse limbs expressing only the G1i3 repressor resemble those of Sonic hedgehog mutants
复制标题
DOI：
10.1016/j.ydbio.2013.04.025
复制
发表时间：
2013-07-15
影响因子：
2.7
通讯作者：
Wang, Baolin
中科院分区：
文献类型：
--
作者：
Cao, Ting;Wang, Chengbing;Wang, Baolin
前后位脊椎动物的肢体模式是由Sonic Hedgehog(Shh)和G1i3转录抑制因子之间的相反作用控制的。出乎意料的是，Gli3(Delta 699)突变小鼠被认为只表达G1i3抑制子而不是全长激活子，表现出与Shh突变小鼠不同的肢体表型。因此，Shh是否主要通过抑制G1i3抑制子的产生来形成前后肢的模式仍有争议。然而，需要注意的是，由于突变等位基因的性质，Gli3(Delta 699)可能不像自然形式的Gli3抑制物那样有效。在本研究中，我们创建了一个条件性Gli3突变等位基因，该等位基因在Cre重组酶存在的情况下唯一表达G1i3抑制因子。利用这个突变体，我们发现只表达G1i3抑制物的小鼠四肢的表型没有或表现为一位数，与Shh突变的四肢相似。与肢体表型一致，依赖Shh信号的基因在两个突变体中的表达也受到抑制。G1i3抑制因子的这种抑制作用不依赖于Shh。因此，我们的研究澄清了目前的争议，并提供了重要的遗传学证据，支持Shh主要通过抑制Gli3抑制物的形成来形成前后肢的假说。(C)2013 Elsevier Inc.保留所有权利。
Anterioposterior vertebrate limb patterning is controlled by opposing action between Sonic Hedgehog (Shh) and the G1i3 transcriptional repressor. Unexpectedly, Gli3(Delta 699) mutant mice, which are thought to express only a G1i3 repressor and not the full-length activator, exhibit limb phenotypes inconsistent with those of Shh mutant mice. Therefore, it remains debatable whether Shh patterns the anterioposterior limb primarily by inhibiting generation of the G1i3 repressor. However, one caveat is that Gli3(Delta 699) may not be as potent as the natural form of Gli3 repressor because of the nature of the mutant allele. In the present study, we created a conditional Gli3 mutant allele that exclusively expresses G1i3 repressor in the presence of Cre recombinase. Using this mutant, we show that the phenotypes of mouse limbs expressing only the G1i3 repressor exhibit no or single digit, resembling those of Shh mutant limbs. Consistent with the limb phenotypes, the expression of genes dependent on Shh signaling is also inhibited in both mutants. This inhibition by the G1i3 repressor is independent of Shh. Thus, our study clarifies the current controversy and provides important genetic evidence to support the hypothesis that Shh patterns the anterioposterior limb primarily through the inhibition of Gli3 repressor formation. (C) 2013 Elsevier Inc. All rights reserved.