Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation.
Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation.
复制标题
DOI：
--
复制
发表时间：
2001-12
期刊：
影响因子：
4.6
通讯作者：
F. Long;Xiaoyan M. Zhang;S. Karp;Yingzi Yang;A. McMahon
中科院分区：
文献类型：
--
作者：
F. Long;Xiaoyan M. Zhang;S. Karp;Yingzi Yang;A. McMahon
印度Hhedgehog(IHH)是哺乳动物三种HH蛋白之一，在软骨内骨发育过程中协调软骨细胞的增殖和分化。平滑蛋白(Smo)是一种转导所有HH信号的跨膜蛋白。为了明确IHH在软骨发育中的直接和间接作用，我们使用了Cre-loxP方法来特异性地去除软骨细胞中的Smo活性。通过这种方式产生的动物与野生型小猫相比，会发育出更短的长骨。与IHH突变体(IHH(N)/IHH(N))相比，软骨细胞分化正常进行。然而，与IHH(N)/IHH(N)小鼠一样，软骨细胞的增殖减少了约50%，这支持了IHH在软骨细胞增殖调节中的直接作用。此外，通过使用双基因UAS-Gal4系统在软骨中特异性地过度表达IHH或结构性活性的Smo等位基因(Smo*)，我们证明了IHH信号通路的激活足以促进软骨细胞的增殖。最后，当IHH或Smo活性从软骨细胞中去除时，细胞周期蛋白D1的表达明显下调，这表明IHH至少部分地通过调节细胞周期蛋白D1的转录来调节软骨细胞的增殖。综上所述，本研究确定IHH是软骨内骨骼中的关键有丝分裂原。
Indian hedgehog (Ihh), one of the three mammalian hedgehog (Hh) proteins, coordinates proliferation and differentiation of chondrocytes during endochondral bone development. Smoothened (Smo) is a transmembrane protein that transduces all Hh signals. In order to discern the direct versus indirect roles of Ihh in cartilage development, we have used the Cre-loxP approach to remove Smo activity specifically in chondrocytes. Animals generated by this means develop shorter long bones when compared to wild-type littermates. In contrast to Ihh mutants (Ihh(n)/Ihh(n)), chondrocyte differentiation proceeds normally. However, like Ihh(n)/Ihh(n) mice, proliferation of chondrocytes is reduced by about 50%, supporting a direct role for Ihh in the regulation of chondrocyte proliferation. Moreover, by overexpressing either Ihh or a constitutively active Smo allele (Smo*) specifically in the cartilage using the bigenic UAS-Gal4 system, we demonstrate that activation of the Ihh signaling pathway is sufficient to promote chondrocyte proliferation. Finally, expression of cyclin D1 is markedly downregulated when either Ihh or Smo activity is removed from chondrocytes, indicating that Ihh regulates chondrocyte proliferation at least in part by modulating the transcription of cyclin D1. Taken together, the present study establishes Ihh as a key mitogen in the endochondral skeleton.