Liu Yang, Feng Jifan, Li Jingyuan, Zhao Hu, Ho Thach-Vu, Chai Yang
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA Department of Prosthodontics, Peking University School and Hospital of Stomatology, Haidian District, Beijing 100081, People's Republic of China.
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA.
Development. 2015 Oct 1;142(19):3374-82. doi: 10.1242/dev.127068. Epub 2015 Aug 20.
Coordination between the Hertwig's epithelial root sheath (HERS) and apical papilla (AP) is crucial for proper tooth root development. The hedgehog (Hh) signaling pathway and Nfic are both involved in tooth root development; however, their relationship has yet to be elucidated. Here, we establish a timecourse of mouse molar root development by histological staining of sections, and we demonstrate that Hh signaling is active before and during root development in the AP and HERS using Gli1 reporter mice. The proper pattern of Hh signaling activity in the AP is crucial for the proliferation of dental mesenchymal cells, because either inhibition with Hh inhibitors or constitutive activation of Hh signaling activity in transgenic mice leads to decreased proliferation in the AP and shorter roots. Moreover, Hh activity is elevated in Nfic(-/-) mice, a root defect model, whereas RNA sequencing and in situ hybridization show that the Hh attenuator Hhip is downregulated. ChIP and RNAscope analyses suggest that Nfic binds to the promoter region of Hhip. Treatment of Nfic(-/-) mice with Hh inhibitor partially restores cell proliferation, AP growth and root development. Taken together, our results demonstrate that an Nfic-Hhip-Hh signaling pathway is crucial for apical papilla growth and proper root formation. This discovery provides insight into the molecular mechanisms regulating tooth root development.
赫特维希上皮根鞘（HERS）与根尖乳头（AP）之间的协调对于牙根的正常发育至关重要。刺猬（Hh）信号通路和Nfic均参与牙根发育；然而，它们之间的关系尚未阐明。在这里，我们通过对切片进行组织学染色建立了小鼠磨牙牙根发育的时间进程，并使用Gli1报告基因小鼠证明Hh信号在AP和HERS的牙根发育之前及期间均处于活跃状态。AP中Hh信号活性的正确模式对于牙间充质细胞的增殖至关重要，因为用Hh抑制剂抑制或在转基因小鼠中组成性激活Hh信号活性都会导致AP中的增殖减少和牙根变短。此外，在牙根缺陷模型Nfic（-/-）小鼠中Hh活性升高，而RNA测序和原位杂交显示Hh衰减器Hhip下调。染色质免疫沉淀（ChIP）和RNAscope分析表明Nfic与Hhip的启动子区域结合。用Hh抑制剂治疗Nfic（-/-）小鼠可部分恢复细胞增殖、AP生长和牙根发育。综上所述，我们的结果表明Nfic-Hhip-Hh信号通路对于根尖乳头生长和正常牙根形成至关重要。这一发现为调节牙根发育的分子机制提供了见解。
