Distinctive role of ACVR1 in dentin formation: requirement for dentin thickness in molars and prevention of osteodentin formation in incisors of mice
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Dentin is a major component of teeth that protects dental pulp and maintains tooth health. Bone morphogenetic protein (BMP) signaling is required for the formation of dentin. Mice lacking a BMP type I receptor, activin A receptor type 1 (ACVR1), in the neural crest display a deformed mandible. Acvr1 is known to be expressed in the dental mesenchyme. However, little is known about how BMP signaling mediated by ACVR1 regulates dentinogenesis. To explore the role of ACVR1 in dentin formation in molars and incisors in mice, Acvr1 was conditionally disrupted in Osterix-expressing cells (designated as cKO). We found that loss of Acvr1 in the dental mesenchyme led to dentin dysplasia in molars and osteodentin formation in incisors. Specifically, the cKO mice exhibited remarkable tooth phenotypes characterized by thinner dentin and thicker predentin, as well as compromised differentiation of odontoblasts in molars. We also found osteodentin formation in the coronal part of the cKO mandibular incisors, which was associated with a reduction in the expression of odontogenic gene Dsp and an increase in the expression of osteogenic gene Bsp, leading to an alteration of cell fate from odontoblasts to osteoblasts. In addition, the expressions of WNT antagonists, Dkk1 and Sost, were downregulated and B-catenin was up-regulated in the cKO incisors, while the expression levels were not changed in the cKO molars, compared with the corresponding controls. Our results indicate the distinct and critical roles of ACVR1 between incisors and molars, which is associated with alterations in the WNT signaling related molecules. This study demonstrates for the first time the physiological roles of ACVR1 during dentinogenesis.
KeywordsBMP signaling Dentinogenesis Odontoblast Osteodentin WNT signaling
The authors thank Dr. Vesa Kaartinen for the Acvr1-floxed mice. This work was supported by grants from the National Key Research and Development Program of China (2016YFC1102800), the Natural Science Foundation of China (81320108011, 81500820, 81600890, 81600843, 81600879 and 81600823), China Postdoctoral Science Foundation (2017M621219 and 2018T110258), the Fundamental Research Funds for the Central Universities, and JLU Science and Technology Innovative Research Team 2017TD-11. YM is supported by a grant from the National Institutes of Health (R01DE020843).
Xue Zhang and Ce Shi contributed to the experimental design, experiment performance, and paper writing; Xue Zhang, Ce Shi, Qilin Liu, Huan Zhao and Xinqing Hao prepared the mouse samples and performed the genotyping; Yue Hu and Cangwei Liu did the HE/IHC stainings; Guangxing Yan analyzed the IHC data; Daowei Li performed the micro-CT scanning and analysis; Xue Zhang, Ce Shi, Qilin Liu, Yuji Mishina and Hongchen Sun prepared and revised the manuscript. All authors have read and approved the final manuscript.
Compliance with ethical standards
Conflicts of interest
There are no conflicts of interest.
Animal use in this study was approved by the Institutional Animal Care and Use Committee of Jilin University, Changchun, People’s Republic of China. The animal experiments were performed in accordance with the requirements of the Experimental Animal Ethics and Welfare guidelines (Permit Number: 20160205).
- Foster BL, Ao M, Willoughby C, Soenjaya Y, Holm E, Lukashova L, Tran AB, Wimer HF, Zerfas PM, Nociti Jr FH, Kantovitz KR, Somerman MJ (2015) Mineralization defects in cementum and craniofacial bone from loss of bone sialoprotein. Bone 78:150–164. https://doi.org/10.1016/j.bone.2015.05.007 Google Scholar
- Kaartinen V, Nagy A (2001) Removal of the floxed neo gene from a conditional knockout allele by the adenoviral Cre recombinase in vivo. Genesis 31(3):126–129Google Scholar
- Lee TY, Lee DS, Kim HM, Ko JS, Gronostajski RM, Cho MI, Son HH, Park JC (2009a) Disruption of Nfic causes dissociation of odontoblasts by interfering with the formation of intercellular junctions and aberrant odontoblast differentiation. J Histochem Cytochem 57(5):469–476. https://doi.org/10.1369/jhc.2009.952622 Google Scholar
- Lee DS, Park JT, Kim HM, Ko JS, Son HH, Gronostajski RM, Cho MI, Choung PH, Park JC (2009b) Nuclear factor I-C is essential for odontogenic cell proliferation and odontoblast differentiation during tooth root development. J Biol Chem 284(25):17293–17303. https://doi.org/10.1074/jbc.M109.009084 Google Scholar
- Macias-Silva M, Hoodless PA, Tang SJ, Buchwald M, Wrana JL (1998) Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. J Biol Chem 273(40):25628–25636Google Scholar
- Meschi N, Hilkens P, Lambrichts I, Van den Eynde K, Mavridou A, Strijbos O, De Ketelaere M, Van Gorp G, Lambrechts P (2016) Regenerative endodontic procedure of an infected immature permanent human tooth: an immunohistological study. Clin Oral Investig 20(4):807–814. https://doi.org/10.1007/s00784-015-1555-8 Google Scholar
- Nose-Ishibashi K, Watahiki J, Yamada K, Maekawa M, Watanabe A, Yamamoto G, Enomoto A, Matsuba Y, Nampo T, Taguchi T, Ichikawa Y, Maki K (2014) Soft-diet feeding after weaning affects behavior in mice: potential increase in vulnerability to mental disorders. Neuroscience 263:257–268. https://doi.org/10.1016/j.neuroscience.2013.12.065 Google Scholar
- Orvis GD, Jamin SP, Kwan KM, Mishina Y, Kaartinen VM, Huang S, Roberts AB, Umans L, Huylebroeck D, Zwijsen A, Wang D, Behringer RR (2008) Functional redundancy of TGF-beta family type I receptors and receptor-Smads in mediating anti-Mullerian hormone-induced Mullerian duct regression in the mouse. Biol Reprod 78(6):994–1001. https://doi.org/10.1095/biolreprod.107.066605 Google Scholar
- Rakian A, Yang WC, Gluhak-Heinrich J, Cui Y, Harris MA, Villarreal D, Feng JQ, MacDougall M, Harris SE (2013) Bone morphogenetic protein-2 gene controls tooth root development in coordination with formation of the periodontium. Int J Oral Sci 5(2):75–84. https://doi.org/10.1038/ijos.2013.41 Google Scholar
- Sfakianou A, Emmanouil DE, Tosios KI, Sklavounou A (2016) Peripheral tumor with osteodentin and cementum-like material in an infant: odontogenic hamartoma or odontoma? J Dent Child (Chic) 83(1):38–41Google Scholar
- Suzuki H, Amizuka N, Kii I, Kawano Y, Nozawa-Inoue K, Suzuki A, Yoshie H, Kudo A, Maeda T (2004) Immunohistochemical localization of periostin in tooth and its surrounding tissues in mouse mandibles during development. Anat Rec A Discov Mol Cell Evol Biol 281(2):1264–1275. https://doi.org/10.1002/ar.a.20080 Google Scholar
- Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, Nagorney DM, Burgart LJ, Roche PC, Smith DI, Ross JA, Liu W (2002) Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 21(31):4863–4871. https://doi.org/10.1038/sj.onc.1205591 Google Scholar
- Yi SE, Daluiski A, Pederson R, Rosen V, Lyons KM (2000) The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb. Development 127(3):621–630Google Scholar