title: An Nfic-hedgehog signaling cascade regulates tooth root development.
abstract: 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.
authors: 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.
authors: Yang
authors: Y
authors: Liu
authors: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA.
authors: Jifan
authors: J
authors: Feng
authors: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing 100050, People's Republic of China.
authors: Jingyuan
authors: J
authors: Li
authors: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA.
authors: Hu
authors: H
authors: Zhao
authors: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA.
authors: Thach-Vu
authors: TV
authors: Ho
authors: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA ychai@usc.edu.
authors: Yang
authors: Y
authors: Chai
mesh_terms: D000818:Animals; D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D005697:Galactosides; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D017403:In Situ Hybridization; D007211:Indoles; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008963:Molar / Q000254:growth & development; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000502:physiology*; D051839:NFI Transcription Factors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000502:physiology*; D013629:Tamoxifen; D014092:Tooth Root / Q000254:growth & development*; D055114:X-Ray Microtomography; D000071676:Zinc Finger Protein GLI1
chemical_list: D017931:DNA Primers; D005697:Galactosides; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D007211:Indoles; D051741:Kruppel-Like Transcription Factors; D051839:NFI Transcription Factors; C497648:Nfic protein, mouse; D000071676:Zinc Finger Protein GLI1; D013629:Tamoxifen; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside
keywords: Mouse; Nfic; Proliferation; Root development; Shh