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Methylation of Cdkn1c may be involved in the regulation of tooth development through cell cycle inhibition.

ABSTRACT: Cdkn1c, a member of the Cip/Kip cyclin-dependent kinase inhibitor family, is critically involved in regulating cell cycle and cellular differentiation during development in mammals. However, the functional role of Cdkn1c and the underlying mechanisms by which Cdkn1c affects odontogenesis remain largely unknown. In our study, we found that Cdkn1c expression dynamically changes from embryonic day 11.5 (E11.5) to postnatal day 3 (P3), and exhibits tissue-specific expression profiles. Evaluation of CDKN1C protein by immunohistochemistry and western blot, revealed that CDKN1C protein expression peaks at P3 and then is reduced at P5 and P7. Interestingly, we observed that CDKN1C expression is higher in immature odontoblasts than preodontoblasts, is lower in mature odontoblasts, and is practically absent from ameloblasts. We evaluated cell cycle progression to further investigate the mechanisms underlying CDKN1C-mediated regulation of odontogenesis, and found that pRB, cyclin D1 and CDK2 expression decreased from P1 to P3, and reduced at P5 and P7. In addition, we observed increased methylation of KvDMR1 at P1 and P3, and reduced KvDMR1 methylation at P5 and P7. However, the methylation levels of Cdkn1c-sDMR were relatively low from P1 to P7. In summary, we demonstrated that Cdkn1c expression and methylation status may be involved in early postnatal tooth development through regulating the cell cycle inhibition activity of Cdkn1c. Notably, Cdkn1c expression and methylation may associate with cell cycle exit and differentiation of odontoblasts.

SUBMITTER: Li Q

PROVIDER: S-EPMC6182578 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Methylation of Cdkn1c may be involved in the regulation of tooth development through cell cycle inhibition.

Li Qiulan Q Guo Yue Y Yao Mianfeng M Li Jun J Chen Yingyi Y Liu Qiong Q Chen Yun Y Zeng Yuanyuan Y Ji Bin B Feng Yunzhi Y

Journal of molecular histology 20180716 5

Cdkn1c, a member of the Cip/Kip cyclin-dependent kinase inhibitor family, is critically involved in regulating cell cycle and cellular differentiation during development in mammals. However, the functional role of Cdkn1c and the underlying mechanisms by which Cdkn1c affects odontogenesis remain largely unknown. In our study, we found that Cdkn1c expression dynamically changes from embryonic day 11.5 (E11.5) to postnatal day 3 (P3), and exhibits tissue-specific expression profiles. Evaluation of ...[more]

PMID: 30014245

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Project description:Murine tooth germ development proceeds in continuous and sequential steps with reciprocal interactions between the odontogenic epithelium and the adjacent mesenchyme, and several growth factor signaling and their activation are required for tooth germ development. The expression of ADP-ribosylation factor (Arf)-like 4c (Arl4c) has been shown to induce cell proliferation, thereby involving in epithelial morphogenesis and tumorigenesis. However, other functions of Arl4c except for cellular growth are largely unknown. Although we recently demonstrated the involvement of the upregulated expression of Arl4c in cell proliferation of ameloblastoma, which has the same origin as odontogenic epithelium, its effect on tooth germ development remains unclear. Herein, single-cell RNA sequencing (scRNA-seq) analysis revealed that the expression of Arl4c, among 17 members of the Arf-family members, was specifically detected in odontogenic epithelial cells, such as stratum intermedium, stella reticulum and outer enamel epithelium, of postnatal day 1 (P1) mouse molar. In addition, scRNA-seq analysis showed higher expression of Arl4c in non-ameloblast and inner enamel epithelium, which include immature cells. In the mouse tooth germ rudiments culture, treatment with SecinH3 (an inhibitor of ARNO/Arf6 pathway) reduced the size, width and cusp height and the thickness of eosinophilic layer, which would involve the synthesis of dentin and enamel matrix organization. In addition, loss-of-function experiments using siRNAs and shRNA revealed that Arl4c expression was involved in cell proliferation and osteoblastic cytodifferentiation in odontogenic epithelial cells. Finally, RNA-seq analysis with gene set enrichment analyses (GSEA) and Gene Ontology (GO) analysis showed that osteoblastic differentiation-related gene set and/or GO terms were downregulated in shArl4c expressing odontogenic epithelial cells. These results suggest that the Arl4c-ARNO/Arf6 pathway axis contributes to tooth germ development through osteoblastic differentiation.

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Methylation of Cdkn1c may be involved in the regulation of tooth development through cell cycle inhibition.

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Methylation of Cdkn1c may be involved in the regulation of tooth development through cell cycle inhibition.

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