miR-145 and miR-143 Regulate Odontoblast Differentiation through Targeting Klf4 and Osx Genes in a Feedback Loop

Dentin tissue is derived from mesenchymal cells induced into the odontoblast lineage. The differentiation of odontoblasts is a complex process regulated by several transcriptional factor signaling transduction pathways. However, post-translational regulation of these factors during dentinogenesis re...

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Bibliographic Details
Published in:The Journal of biological chemistry 2013-03, Vol.288 (13), p.9261-9271
Main Authors: Liu, Huan, Lin, Heng, Zhang, Li, Sun, Qin, Yuan, Guohua, Zhang, Lu, Chen, Shuo, Chen, Zhi
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Amino Acid Motifs
Animals
Cell Biology
Cell Differentiation
Cell Line
Chromatin Immunoprecipitation
Dentin
Dentin - metabolism
Differentiation
Gene Expression Regulation, Developmental
In Situ Hybridization
Kruppel-like factor (KLF)
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors - metabolism
Krüpple-like Factor 4 (Klf4)
Mice
MicroRNA
MicroRNA-143
MicroRNA-145
MicroRNAs - metabolism
Odontoblast
Odontoblasts - cytology
Odontoblasts - metabolism
Oligonucleotide Array Sequence Analysis
Osterix (Osx)
Signal Transduction
Sp7 Transcription Factor
Time Factors
Tooth - embryology
Tooth Development
Transcription Factors - metabolism
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Summary:Dentin tissue is derived from mesenchymal cells induced into the odontoblast lineage. The differentiation of odontoblasts is a complex process regulated by several transcriptional factor signaling transduction pathways. However, post-translational regulation of these factors during dentinogenesis remains unclear. To further explore the mechanisms, we investigated the role of microRNA (miRNA) during odontoblast differentiation. We profiled the miRNA expression pattern during mouse odontoblast differentiation using a microarray assay and identified that miR-145 and miR-143 were down-regulated during this process. In situ hybridization verified that the two miRNAs were gradually decreased during mouse odontoblast differentiation. Loss-of-function and gain-of-function experiments revealed that down-regulation of miR-145 and miR-143 could promote odontoblast differentiation and increased Dspp and Dmp1 expression in mouse primary dental pulp cells and vice versa. We found that miR-145 and miR-143 controlled odontoblast differentiation through several mechanisms. First, KLF4 and OSX bind to their motifs in Dspp and Dmp1 gene promoters and up-regulate their transcription thereby inducing odontoblast differentiation. The miR-145 binds to the 3′-UTRs of Klf4 and Osx genes, inhibiting their expression. Second, KLF4 repressed miR-143 transcription by binding to its motifs in miR-143 regulatory regions as detected by ChIP assay and dual luciferase reporter assay. Third, miR-143 regulates odontoblast differentiation in part through miR-145 pathway. Taken together, we for the first time showed that the miR-143 and miR-145 controlled odontoblast differentiation and dentin formation through KLF4 and OSX transcriptional factor signaling pathways. Background: miRNAs are crucial in orchestrating the odontoblast differentiation through negatively regulating their target gene expression. Results: miR-143, which is repressed by KLF4, can promote miR-145 expression, whereas the latter inhibits KLF4, which promotes odontoblast differentiation. Conclusion: miR-143, miR-145, and KLF4 form a feedback loop in odontoblast. Significance: This is the first report on feedback loop regulation of odontoblast differentiation in which miRNAs are involved.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M112.433730