A SHH-independent regulation of Gli3 is a significant determinant of anteroposterior patterning of the limb bud
A SHH-independent regulation of Gli3 is a significant determinant of anteroposterior patterning of the limb bud
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DOI：
10.1016/j.ydbio.2009.02.017
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发表时间：
2009-04-15
影响因子：
2.7
通讯作者：
Ruether, Ulrich
中科院分区：
文献类型：
--
作者：
Hill, Patrick;Goetz, Katrin;Ruether, Ulrich
GLI 蛋白家族 (GLI1-3) 包含刺猬通路的细胞内介质，该通路调节多种发育过程，其中之一是肢体发育。虽然 GLI1 和 GLI2 在肢体发育过程中似乎是可有可无的，但 GLI3 尤为重要，因为所有与 GLI3 相关的人类先天性疾病都包括肢体畸形。此外，Gli3(-/-) 小鼠胚胎表现出明显的多指畸形以及数字身份的丧失。在这里，我们通过使用不同的 Gli3 突变体来检查 GLI3 的数量如何对其功能做出贡献，以改变总体 GLI3 水平。此外，我们还利用了 Gli3(Delta 699) 等位基因，它编码 GLI3 的 C 端截短版本，从而模仿了加工后的 GLI3 亚型 (GLI3R)。 Gli3（Delta 699）突变体使得在肢芽的前后模式背景下分析 GLI3 的异构体特异性贡献成为可能。我们揭示了远端肢体形成的不同阶段和方面对 GLI3 的数量需求的迄今为止未被认识到的变化。此外，我们的分析提供了证据，表明未经处理的全长 GLI3 对于肢芽的前后模式是可有可无的。相反，数字身份很可能仅由 GLI3 抑制子活性来定义。此外，我们提出的证据表明，SHH 的作用对 GLI3 活性的前后分级得到了原型模式的支持，该原型模式独立于 SHH 调节 Gli3。 (C) 2009 Elsevier Inc. 保留所有权利。
The family of GLI proteins (GLI1-3) comprises the intracellular mediators of the hedgehog pathway, which regulates a myriad of developmental processes, one of which is limb development. Whereas GLI1 and GLI2 seem to be dispensable during limb development, GLI3 is especially crucial since all GLI3-associated human congenital diseases comprise limb malformations. Furthermore, Gli3(-/-) mouse embryos exhibit pronounced polydactyly in conjunction with a loss of digit identities.Here we examined how the quantity of GLI3 contributes to its function by using different Gli3 mutants in order to vary overall GLI3 levels. In addition, we made use of the Gli3(Delta 699) allele, which encodes a C-terminally truncated version of GLI3, thus mimicking the processed GLI3 isoform (GLI3R). The Gli3(Delta 699) mutant made it feasible to analyze isoform-specific contributions of GLI3 within the context of anteroposterior patterning of the limb bud. We revealed a so far unappreciated variation in the quantitative demand for GLI3 within different phases and aspects of distal limb formation. In addition, our analyses provide evidence that unprocessed full-length GLI3 is dispensable for anteroposterior patterning of the limb bud. Instead, digit identities are most likely defined by GLI3 repressor activity alone. Furthermore, we present evidence that the anteroposterior grading of GLI3 activity by the action of SHH is supported by a prototype patterning, which regulates Gli3 independently from SHH. (C) 2009 Elsevier Inc. All rights reserved.