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).
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