Mill Pleasantine, Mo Rong, Hu Ming Chang, Dagnino Lina, Rosenblum Norman D, Hui Chi-Chung
Department of Medical and Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
Dev Cell. 2005 Aug;9(2):293-303. doi: 10.1016/j.devcel.2005.05.009.
Shh signaling induces proliferation of many cell types during development and disease, but how Gli transcription factors regulate these mitogenic responses remains unclear. By genetically altering levels of Gli activator and repressor functions in mice, we have demonstrated that both Gli functions are involved in the transcriptional control of N-myc and Cyclin D2 during embryonic hair follicle development. Our results also indicate that additional Gli-activator-dependent functions are required for robust mitogenic responses in regions of high Shh signaling. Through posttranscriptional mechanisms, including inhibition of GSK3-beta activity, Shh signaling leads to spatially restricted accumulation of N-myc and coordinated cell cycle progression. Furthermore, a temporal shift in the regulation of GSK3-beta activity occurs during embryonic hair follicle development, resulting in a synergy with beta-catenin signaling to promote coordinated proliferation. These findings demonstrate that Shh signaling controls the rapid and patterned expansion of epithelial progenitors through convergent Gli-mediated regulation.
在发育和疾病过程中，音猬因子（Shh）信号传导可诱导多种细胞类型的增殖，但Gli转录因子如何调节这些促有丝分裂反应仍不清楚。通过基因改变小鼠中Gli激活剂和阻遏物功能的水平，我们已经证明，在胚胎毛囊发育过程中，Gli的这两种功能都参与了对N - myc和细胞周期蛋白D2的转录控制。我们的结果还表明，在高Shh信号区域，强大的促有丝分裂反应需要额外的Gli激活剂依赖性功能。通过包括抑制糖原合成酶激酶3β（GSK3 - β）活性在内的转录后机制，Shh信号传导导致N - myc在空间上受限的积累以及协调的细胞周期进程。此外，在胚胎毛囊发育过程中，GSK3 - β活性的调节发生了时间上的转变，导致与β - 连环蛋白信号传导协同作用以促进协调的增殖。这些发现表明，Shh信号传导通过Gli介导的趋同调节来控制上皮祖细胞的快速且有模式的扩增。
