Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway.
Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway.
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发表时间：
2002-10
期刊：
影响因子：
4.6
通讯作者：
C. B. Bai;W. Auerbach;Joon‐Sung Lee;Daniel N. Stephen;A. Joyner
中科院分区：
文献类型：
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作者：
C. B. Bai;W. Auerbach;Joon‐Sung Lee;Daniel N. Stephen;A. Joyner
许多哺乳动物组织的胚胎模式、细胞增殖和分化都需要 Shh 信号通路。此外，该途径的不适当激活与许多人类肿瘤有关。基于青蛙和小鼠的转染测定和功能获得研究，转录因子 Gli1 被认为是 Shh 信号传导的主要介质。为了解决小鼠中是否存在这种情况，我们生成了表达 lacZ 的 Gli1 无效等位基因。引人注目的是，Gli1 并不是小鼠发育或生存所必需的。相关的是，我们发现神经系统和四肢中 Gli1 的所有转录都依赖于 Shh，因此，Gli1 蛋白通常不存在来转导初始的 Shh 信号传导。为了确定 Gli1 是否会导致 Shh 通路不当激活和诱导 Gli1 转录时出现的缺陷，生成了 Gli1;Ptc 双突变体。我们发现，Gli1 不是 Shh 信号通路异位激活或 Ptc 无效突变体中早期胚胎致死表型所必需的。重要的是，我们发现 Gli2 是介导 Ptc 突变体中一些不适当的 Shh 信号传导所必需的。我们的研究表明，在哺乳动物中，Shh 信号传导不需要 Gli1，而 Gli2 由于负调节因子 Ptc 的缺失而介导该通路的不适当激活。
The Shh signaling pathway is required in many mammalian tissues for embryonic patterning, cell proliferation and differentiation. In addition, inappropriate activation of the pathway has been implicated in many human tumors. Based on transfection assays and gain-of-function studies in frog and mouse, the transcription factor Gli1 has been proposed to be a major mediator of Shh signaling. To address whether this is the case in mouse, we generated a Gli1 null allele expressing lacZ. Strikingly, Gli1 is not required for mouse development or viability. Of relevance, we show that all transcription of Gli1 in the nervous system and limbs is dependent on Shh and, consequently, Gli1 protein is normally not present to transduce initial Shh signaling. To determine whether Gli1 contributes to the defects seen when the Shh pathway is inappropriately activated and Gli1 transcription is induced, Gli1;Ptc double mutants were generated. We show that Gli1 is not required for the ectopic activation of the Shh signaling pathway or to the early embryonic lethal phenotype in Ptc null mutants. Of significance, we found instead that Gli2 is required for mediating some of the inappropriate Shh signaling in Ptc mutants. Our studies demonstrate that, in mammals, Gli1 is not required for Shh signaling and that Gli2 mediates inappropriate activation of the pathway due to loss of the negative regulator Ptc.