The Gli2 transcriptional activator is a crucial effector for Ihh signaling in osteoblast development and cartilage vascularization
The Gli2 transcriptional activator is a crucial effector for Ihh signaling in osteoblast development and cartilage vascularization
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DOI：
10.1242/dev.041624
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发表时间：
2009-12-15
期刊：
影响因子：
4.6
通讯作者：
Long, Fanxin
中科院分区：
文献类型：
--
作者：
Joeng, Kyu Sang;Long, Fanxin
Indian hedgehog（Ihh）严格调节软骨内骨发育的多个方面。虽然人们普遍认为所有的Ihh功能都是由Gli家族的转录激活因子和抑制因子介导的，但这一概念的正式遗传学证据尚未提供。此外，不同Gli蛋白对Ihh功能的贡献程度尚未完全了解。以前的工作表明，Gli 3阻遏物的去阻遏是Ihh控制软骨细胞增殖和成熟的主要模式，但成骨细胞分化和肥大软骨血管化需要额外的机制。为了测试Gli 2激活在这些过程中的参与，我们已经产生了一种小鼠品系，其以Cre依赖的方式表达组成型Gli 2激活剂，并试图用Gli 2激活剂单独或与Gli 3去除组合来拯救Ihh-null小鼠。在这里，我们报告说，单独的Gli 2激活剂是足够的诱导血管化的肥大软骨在IHH的情况下，但需要同时去除Gli 3恢复成骨细胞分化。因此，这些结果提供了直接的遗传学证据，Gli 2和Gli 3共同介导的所有主要方面的Ihh功能在endochondrial骨骼发育。
Indian hedgehog (Ihh) critically regulates multiple aspects of endochondral bone development. Although it is generally believed that all Ihh functions are mediated by the Gli family of transcription activators and repressors, formal genetic proof for this notion has not been provided. Moreover, the extent to which different Gli proteins contribute to Ihh functions is not fully understood. Previous work has shown that de-repression of the Gli3 repressor is the predominant mode through which Ihh controls chondrocyte proliferation and maturation, but that osteoblast differentiation and hypertrophic cartilage vascularization require additional mechanisms. To test the involvement of Gli2 activation in these processes, we have generated a mouse strain that expresses a constitutive Gli2 activator in a Cre-dependent manner, and have attempted to rescue the Ihh-null mouse with the Gli2 activator, either alone or in combination with Gli3 removal. Here, we report that the Gli2 activator alone is sufficient to induce vascularization of the hypertrophic cartilage in the absence of Ihh but requires simultaneous removal of Gli3 to restore osteoblast differentiation. These results therefore provide direct genetic evidence that Gli2 and Gli3 collectively mediate all major aspects of Ihh function during endochondral skeletal development.