Functional compensation in Hedgehog signaling during mouse prostate development
Functional compensation in Hedgehog signaling during mouse prostate development
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DOI：
10.1016/j.ydbio.2005.12.002
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发表时间：
2006-07-01
影响因子：
2.7
通讯作者：
Bushman, Wade
中科院分区：
文献类型：
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作者：
Doles, Jason;Cook, Crist;Bushman, Wade
使用抗Shh抗体、hedgehog信号化学抑制剂和Shh（-/-）突变小鼠对前列腺发育中的hedgehog信号进行的研究，在hedgehog信号对正常导管出芽和腺体形态发生的要求方面，得出了相互矛盾的数据。我们使用转基因小鼠模型联合化学抑制剂和肾移植来阐明Hh信号在前列腺发育中的作用。这些研究表明，Shh的遗传缺失伴随着印度刺猬（Ihh）的上调和Hh通路活性的维持。我们发现，虽然正常前列腺导管出芽既不需要GO也不需要Gli3，但Gli2（-/-）突变小鼠的泌尿生殖窦（UGS）在子宫内显示出异常的导管出芽。当作为囊下移植物生长时，Gli2(-/-) UGS表现出前列腺分化，但也表现出局灶性上皮增生。三种Gli转录因子之间的功能冗余似乎减轻了Gli2 LOF的影响，E14 Gli2(-/-) UGS中残留的Hh通路活性可以被环巴胺治疗抑制。总之，这些研究揭示了在配体水平和转录调节水平上运行的令人惊讶的功能冗余程度，有效地减轻了与hh信号扰动相关的表型。(c) 2005爱思唯尔公司版权所有。
Studies of hedgehog signaling in prostate development using anti-Shh antibodies, chemical inhibitors of hedgehog signaling and Shh(-/-) mutant mice have yielded conflicting data regarding the requirements of hedgehog signaling for normal ductal budding and glandular morphogenesis. We used transgenic mouse models in combination with chemical inhibitors and renal grafting to clarify the role of Hh signaling in prostate development. These studies showed that genetic loss of Shh is accompanied by an up-regulation of Indian Hedgehog (Ihh) and maintenance of Hh pathway activity. We found that while neither GO nor Gli3 are required for normal prostate ductal budding, the urogenital sinus (UGS) of the Gli2(-/-) mutant mouse displays aberrant ductal budding in utero. When grown as a subcapsular graft, the Gli2(-/-) UGS exhibited prostatic differentiation but also displayed areas of focal epithelial hyperplasia. Functional redundancy between the three Gli transcription factors appears to mitigate the effect of Gli2 LOF as evidenced by residual Hh pathway activity in the E14 Gli2(-/-) UGS that could be inhibited by cyclopamine treatment. Together, these studies reveal a surprising degree of functional redundancy operating both at the level of the ligand and at the level of transcriptional regulation that effectively mitigates phenotypes associated with Hh-signaling perturbations. (c) 2005 Elsevier Inc. All rights reserved.