Neural Crest Deletion of Dlx3 Leads to Major Dentin Defects through Down-regulation of Dspp

Duverger, Olivier; Zah, Angela; Isaac, Juliane; Sun, Hongwei; Bartels, Anne K.; Lian, Jane B.; Berdal, Ariane; Hwang, Joonsung; Morasso, María I.

doi:10.1074/jbc.m111.326900

Cited by 66 publications

(77 citation statements)

References 53 publications

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“…We observed similar inhibitory effects of miR-665 overexpression on the expression of Mmp20 and Klk4 (Fig. 3D), already reported as downstream targets of Dlx3 essential for tooth matrix formation (30). Similar inhibition of dentinogenesis was also observed on day 7 of odontoblast differentiation in miR-665-overexpressing cells.…”

Section: Discovery Of Mir-665supporting

confidence: 87%

“…Studies from several research groups have revealed that homeodomain gene Dlx3 (Online Mendelian Inheritance in Man [OMIM] entry 600525) is a highly critical regulator of craniofacial and postnatal skeletal development (28)(29)(30)(31)(32)(33)(34). Mutations in DLX3 in humans have been associated with tricho-dento-osseous syndrome (TDO; OMIM 190320) and amelogenesis imperfecta with taurodontism (AIHHT; OMIM 104510), both of which are conditions characterized by abnormalities in tooth formation (35)(36)(37)(38)(39).…”

mentioning

confidence: 99%

“…Expression of DLX3 in postmigratory neural crest cells (E9.5) helps commit these cells to further differentiate into odontoblasts and cementoblasts, contributing to formation of mature dentin and cementum for proper tooth formation (40). Recently, Dspp was identified as a direct target of DLX3 in odontoblasts (30). This is the first mechanistic link established between the transcription factor DLX3 and the dentin matrix protein DSPP, both known to be mutated in human disorders associated with tooth abnormalities (29,30).…”

mentioning

confidence: 99%

“…Recently, Dspp was identified as a direct target of DLX3 in odontoblasts (30). This is the first mechanistic link established between the transcription factor DLX3 and the dentin matrix protein DSPP, both known to be mutated in human disorders associated with tooth abnormalities (29,30). Despite the known role of DLX3 in the development of bone and tooth phenotypes, the mechanism(s) of the posttranscriptional regulation of Dlx3 by miRNA during dentinogenesis is still unclear.…”

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confidence: 99%

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MicroRNA 665 Regulates Dentinogenesis through MicroRNA-Mediated Silencing and Epigenetic Mechanisms

Heair

Kemper

Roy

et al. 2015

Molecular and Cellular Biology

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bStudies of proteins involved in microRNA (miRNA) processing, maturation, and silencing have indicated the importance of miRNAs in skeletogenesis, but the specific miRNAs involved in this process are incompletely defined. Here, we identified miRNA 665 (miR-665) as a potential repressor of odontoblast maturation. Studies with cultured cell lines and primary embryonic cells showed that miR-665 represses the expression of early and late odontoblast marker genes and stage-specific proteases involved in dentin maturation. Notably, miR-665 directly targeted Dlx3 mRNA and decreased Dlx3 expression. Furthermore, RNA-induced silencing complex (RISC) immunoprecipitation and biotin-labeled miR-665 pulldown studies identified Kat6a as another potential target of miR-665. KAT6A interacted physically and functionally with RUNX2, activating tissue-specific promoter activity and prompting odontoblast differentiation. Overexpression of miR-665 reduced the recruitment of KAT6A to Dspp and Dmp1 promoters and prevented KAT6A-induced chromatin remodeling, repressing gene transcription. Taken together, our results provide novel molecular evidence that miR-665 functions in an miRNA-epigenetic regulatory network to control dentinogenesis. D entinogenesis is the process by which dentin, the major mineralized tissue of teeth, is formed through progressive cytodifferentiation of progenitor cells to mature odontoblasts (1). Multiple layers of gene regulation, including those by microRNA (miRNA), orchestrate the physiologic process of dentinogenesis in a stage-specific manner (2). Progenitor cells, including dental papilla cells or dental follicle cells, derived from the ectomesenchyme of the cranial neural crest, differentiate into preodontoblasts and produce predentin. Predentin stimulates further differentiation of the cells it surrounds, giving rise to mature odontoblasts that produce dentin. Odontoblast secretion of dentin extracellular matrix proteins, including dentin sialophosphoprotein (DSPP) and dentin matrix protein 1 (DMP1), aids in the process of mineralization that forms primary dentin. However, the mechanisms of odontoblast-specific gene regulation by miRNA during dentinogenesis are not clearly understood.miRNAs are endogenous, noncoding RNAs implicated in posttranscriptional RNA silencing (3-9). The importance of miRNAs in skeletogenesis has been shown in mice by loss-offunction analysis of proteins involved in miRNA processing (Drosha and DGCR8), maturation (Dicer), and silencing (argonaute 2; AGO2), which revealed embryonic lethality and severe developmental defects upon loss of these proteins (10-15). Furthermore, cartilage-specific deletion of Dicer led to accelerated differentiation and subsequent cell death (11), whereas osteoblast-and osteoclast-specific deletion increased bone mass (13,16). Current studies on miRNA regulation of gene expression indicate a key role for this process in tooth development (17)(18)(19)(20) and in controlling cellular signaling (18,(21)(22)(23)(24)(25) and differentiation (2,26). However, ...

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Section: Discovery Of Mir-665supporting

confidence: 87%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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MicroRNA 665 Regulates Dentinogenesis through MicroRNA-Mediated Silencing and Epigenetic Mechanisms

Heair

Kemper

Roy

et al. 2015

Molecular and Cellular Biology

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“…Therefore, we tested the expressions of three molecular markers: a homeodomain-containing transcription factor, Dlx3, and two odontoblast differentiation markers, Col1a1 and biglycan. Dlx3 has been shown to regulate dentinogenesis through directly regulating Dspp expression (33). We found that Dlx3 was expressed predominantly in the odontoblasts of WT (Fig.…”

Section: Transgenic Expression Of Dspp Rescued the Dentin Mineralizatmentioning

confidence: 67%

The Rescue of Dentin Matrix Protein 1 (DMP1)-deficient Tooth Defects by the Transgenic Expression of Dentin Sialophosphoprotein (DSPP) Indicates That DSPP Is a Downstream Effector Molecule of DMP1 in Dentinogenesis

Gibson

Zhu

Wang

et al. 2013

Journal of Biological Chemistry

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Background:Previous in vitro studies indicated that dentin matrix protein 1 (DMP1) might regulate dentin sialophosphoprotein (DSPP) expression in odontoblasts. Results: Transgenic expression of DSPP rescued the tooth defects of Dmp1 knockout mice. Conclusion: DSPP is a downstream effector molecule of DMP1 in dentinogenesis. Significance: This study has identified the in vivo functional relationship of DMP1 and DSPP in dentinogenesis.

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The Importance of Maintaining Pulp Vitality

Cavalcanti,

Chiego

2024

Vital Pulp Treatment

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Neural Crest Deletion of Dlx3 Leads to Major Dentin Defects through Down-regulation of Dspp

Cited by 66 publications

References 53 publications

MicroRNA 665 Regulates Dentinogenesis through MicroRNA-Mediated Silencing and Epigenetic Mechanisms

MicroRNA 665 Regulates Dentinogenesis through MicroRNA-Mediated Silencing and Epigenetic Mechanisms

The Rescue of Dentin Matrix Protein 1 (DMP1)-deficient Tooth Defects by the Transgenic Expression of Dentin Sialophosphoprotein (DSPP) Indicates That DSPP Is a Downstream Effector Molecule of DMP1 in Dentinogenesis

The Importance of Maintaining Pulp Vitality

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