Program in Developmental & Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Development. 2011 Sep;138(17):3791-801. doi: 10.1242/dev.069492. Epub 2011 Jul 27.
Proper regulation of Indian hedgehog (Ihh) signaling is vital for chondrocyte proliferation and differentiation in the growth plate. Its dysregulation causes skeletal dysplasia, osteoarthritis or cartilaginous neoplasia. Here, we show that Suppressor of fused (Sufu) and Kif7 are essential regulators of Ihh signaling. While Sufu acts as a negative regulator of Gli transcription factors, Kif7 functions both positively and negatively in chondrocytes. Kif7 plays a role in the turnover of Sufu and the exclusion of Sufu-Gli complexes from the primary cilium. Importantly, halving the dose of Sufu restores normal hedgehog pathway activity and chondrocyte development in Kif7-null mice, demonstrating that the positive role of Kif7 is to restrict the inhibitory activity of Sufu. Furthermore, Kif7 also inhibits Gli transcriptional activity in the chondrocytes when Sufu function is absent. Therefore, Kif7 regulates the activity of Gli transcription factors through both Sufu-dependent and -independent mechanisms.
正确调节印度刺猬（Ihh）信号对生长板中的软骨细胞增殖和分化至关重要。其失调会导致骨骼发育不良、骨关节炎或软骨肿瘤。在这里，我们表明融合抑制因子（Sufu）和 Kif7 是 Ihh 信号的重要调节因子。虽然 Sufu 作为 Gli 转录因子的负调节剂起作用，但 Kif7 在软骨细胞中既具有正调节作用，也具有负调节作用。Kif7 在 Sufu 的周转和 Sufu-Gli 复合物从初级纤毛中的排除中起作用。重要的是，将 Sufu 的剂量减半可恢复 Kif7 缺失小鼠中正常的刺猬通路活性和软骨细胞发育，表明 Kif7 的正作用是限制 Sufu 的抑制活性。此外，当 Sufu 功能缺失时，Kif7 也会抑制软骨细胞中的 Gli 转录活性。因此，Kif7 通过 Sufu 依赖和独立的机制来调节 Gli 转录因子的活性。
