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Inactivation of Fam20B in the dental epithelium of mice leads to supernumerary incisors.

ABSTRACT: Tooth formation is tightly regulated by epithelial-mesenchymal interactions via hierarchic cascades of signaling molecules. The glycosaminoglycan (GAG) chains covalently attached to the core protein of proteoglycans (PGs) provide docking sites for signaling molecules and their receptors during the morphogenesis of tissues and organs. Although PGs are believed to play important roles in tooth formation, little is known about their exact functions in this developmental process and the relevant molecular basis. Family with sequence similarity member 20-B (FAM20B) is a newly identified kinase that phosphorylates the xylose in the common linkage region connecting the GAG with the protein core of PGs. The phosphorylation of xylose is essential for elongation of the common linkage region and the subsequent GAG assembly. In this study, we generated a Fam20B-floxed allele in mice and found that inactivating Fam20B in the dental epithelium leads to supernumerary maxillary and mandibular incisors. This finding highlights the pivotal role of PGs in tooth morphogenesis and opens a new window for understanding the regulatory mechanism of PG-mediated signaling cascades during tooth formation.

SUBMITTER: Tian Y

PROVIDER: S-EPMC4662618 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Inactivation of Fam20B in the dental epithelium of mice leads to supernumerary incisors.

Tian Ye Y Ma Pan P Liu Chao C Yang Xiudong X Crawford Derrick M DM Yan Wenjuan W Bai Ding D Qin Chunlin C Wang Xiaofang X

European journal of oral sciences 20151014 6

Tooth formation is tightly regulated by epithelial-mesenchymal interactions via hierarchic cascades of signaling molecules. The glycosaminoglycan (GAG) chains covalently attached to the core protein of proteoglycans (PGs) provide docking sites for signaling molecules and their receptors during the morphogenesis of tissues and organs. Although PGs are believed to play important roles in tooth formation, little is known about their exact functions in this developmental process and the relevant mol ...[more]

PMID: 26465965

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Project description:Family with sequence similarity 20,-member C (FAM20C) is highly expressed in the mineralized tissues of mammals. Genetic studies showed that the loss-of-function mutations in FAM20C were associated with human lethal osteosclerotic bone dysplasia (Raine Syndrome), implying an inhibitory role of this molecule in bone formation. However, in vitro gain- and loss-of-function studies suggested that FAM20C promotes the differentiation and mineralization of mouse mesenchymal cells and odontoblasts. Recently, we generated Fam20c conditional knockout (cKO) mice in which Fam20c was globally inactivated (by crossbreeding with Sox2-Cre mice) or inactivated specifically in the mineralized tissues (by crossbreeding with 3.6 kb Col 1a1-Cre mice). Fam20c transgenic mice were also generated and crossbred with Fam20c cKO mice to introduce the transgene in the knockout background. In vitro gain- and loss-of-function were examined by adding recombinant FAM20C to MC3T3-E1 cells and by lentiviral shRNA-mediated knockdown of FAM20C in human and mouse osteogenic cell lines. Surprisingly, both the global and mineralized tissue-specific cKO mice developed hypophosphatemic rickets (but not osteosclerosis), along with a significant downregulation of osteoblast differentiation markers and a dramatic elevation of fibroblast growth factor 23 (FGF23) in the serum and bone. The mice expressing the Fam20c transgene in the wild-type background showed no abnormalities, while the expression of the Fam20c transgene fully rescued the skeletal defects in the cKO mice. Recombinant FAM20C promoted the differentiation and mineralization of MC3T3-E1 cells. Knockdown of FAM20C led to a remarkable downregulation of DMP1, along with a significant upregulation of FGF23 in both human and mouse osteogenic cell lines. These results indicate that FAM20C is a bone formation "promoter" but not an "inhibitor" in mouse osteogenesis. We conclude that FAM20C may regulate osteogenesis through its direct role in facilitating osteoblast differentiation and its systemic regulation of phosphate homeostasis via the mediation of FGF23.

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Inactivation of Fam20B in the dental epithelium of mice leads to supernumerary incisors.

Publications

Inactivation of Fam20B in the dental epithelium of mice leads to supernumerary incisors.

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