Ablation of Fam20c causes amelogenesis imperfecta via inhibiting Smad dependent BMP signaling pathway

Jing Liu,Lili Li,Wuliji Saiyin,Limin Mao,Xiaohua Xie

doi:10.1186/s13062-020-00270-7

Jing Liu, Lili Li + Show 3 more

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https://doi.org/10.1186/s13062-020-00270-7

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Abstract

BackgroundAmelogenesis imperfecta (AI) is a type of hereditary diseases that manifest defects in the formation or mineralization of enamel. Recently, it is reported that inactivation of FAM20C, a well-known Golgi casein kinase, caused AI. However, the mechanism of it is still unknown. The aim of this study was to explore the molecular mechanism of AI, which caused by ablation of FAM20C.ResultsIn the Sox2-Cre;Fam20Cfl/fl (cKO) mouse, we found abnormal differentiation of ameloblasts, improper formation and mineralization of enamel, and downregulation of both mRNA and protein level of enamel matrix proteins, including amelogenin (AMEL), ameloblastin (AMBN) and enamelin (ENAM). The levels of BMP2, BMP4 and BMP7, the ligands of BMP signaling pathway, and phosphorylation of Smad1/5/8, the key regulators of BMP signaling pathway, were all decreased in the enamel matrix and the ameloblast of the cKO mice, respectively. The expression of cyclin-dependent kinase inhibitor (P21), muscle segment homeobox genes 2 (Msx2), which are the target genes of the BMP signaling pathway, and laminin 3, the downstream factor of Msx2, were all significantly decreased in the ameloblasts of the cKO mice compared to the control mice.Conclusionthe results of our study suggest that ablation of FAM20C leads to AI through inhibiting the Smad dependent BMP signaling pathway in the process of amelogenesis.

Highlights

Amelogenesis imperfecta (AI) is a type of hereditary diseases that manifest defects in the formation or mineralization of enamel
Ablation of Fam20C causes AI The cKO mice showed apparent enamel defects compared to the normal controls
We noticed some lower density sedimentlike tissues located between the alveolar bone and the labial side of incisors in the cKO mice (Fig. 2E). Micro-computed Tomography (μCT) analysis showed that the incisors had a distinct layer of enamel formed on their labial side in the control mice whereas a layer of ectopic calcifications, in place of enamel, was found on the labial side of the incisors in the cKO mice

Summary

Introduction

Amelogenesis imperfecta (AI) is a type of hereditary diseases that manifest defects in the formation or mineralization of enamel. Results: In the Sox2-Cre;Fam20Cfl/fl (cKO) mouse, we found abnormal differentiation of ameloblasts, improper formation and mineralization of enamel, and downregulation of both mRNA and protein level of enamel matrix proteins, including amelogenin (AMEL), ameloblastin (AMBN) and enamelin (ENAM). The levels of BMP2, BMP4 and BMP7, the ligands of BMP signaling pathway, and phosphorylation of Smad1/5/8, the key regulators of BMP signaling pathway, were all decreased in the enamel matrix and the ameloblast of the cKO mice, respectively. Ameloblasts secreted abundant enamel matrix proteins (EMPs), such as amelogenin (AMEL), ameloblastin (AMBN) and enamelin (ENAM), and numerous cell adhesion molecules and it is reported that mutations of these EMPs will cause Hypoplastic AI in human [2,3,4,5,6,7]. Beside the EMPs and the enamel matrix proteases, dysfunction of some growth factors, which regulating

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