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1.  Molecular and circadian controls of ameloblasts 
European journal of oral sciences  2011;119(Suppl 1):35-40.
Stage-specific expression of ameloblast-specific genes is controlled by differential expression of transcription factors. In addition, ameloblasts follow daily rhythms in their main activities i.e. enamel protein secretion and enamel mineralization. This time related control is orchestrated by oscillations of clock proteins involved in circadian rhythms regulation. Our aim was to identify the potential links between daily rhythms and developmental controls of ameloblast differentiation. The effects of selected transcriptional factors Distal-less homeobox 3 (Dlx3) and Runt related transcription factor 2 (Runx2) and clock gene Nuclear receptor subfamily 1, group D, member 1 (Nr1d1) on secretory and maturation ameloblasts [using stage-specific markers amelogenin (Amel), enamelin (Enam) and kallikrein related-peptidase 4 (Klk4)] were evaluated in HAT-7 ameloblast cell line. Amel and Enam steady-state RNA expression levels were down-regulated in Runx2 over-expressing cells and up-regulated in Dlx3 over-expressing cells. In contrast, Klk4 was up-regulated by both Dlx3 and Runx2. Furthermore, a temporal and spatial relationship between clock genes and ameloblast differentiation markers was detected. Of interest, clock genes not only affected rhythmic expression of ameloblast specific genes but also influenced the expression of Runx2. Multi-scale mathematical modeling is being explored to further understand the temporal and developmental controls of ameloblast differentiation. Our study provides novel insights into the regulatory mechanisms sustaining ameloblast differentiation.
doi:10.1111/j.1600-0722.2011.00918.x
PMCID: PMC3516856  PMID: 22243224
Ameloblast gene regulation; circadian rhythms; clock genes; multi-scale modeling; enamel
2.  Tissue Regeneration in Dentistry 
doi:10.1155/2012/586701
PMCID: PMC3362032  PMID: 22666252
3.  Innovative Approaches to Regenerate Enamel and Dentin 
The process of tooth mineralization and the role of molecular control of cellular behavior during embryonic tooth development have attracted much attention the last few years. The knowledge gained from the research in these fields has improved the general understanding about the formation of dental tissues and the entire tooth and set the basis for teeth regeneration. Tissue engineering using scaffold and cell aggregate methods has been considered to produce bioengineered dental tissues, while dental stem/progenitor cells, which can differentiate into dental cell lineages, have been also introduced into the field of tooth mineralization and regeneration. Some of the main strategies for making enamel, dentin, and complex tooth-like structures are presented in this paper. However, there are still significant barriers that obstruct such strategies to move into the regular clinic practice, and these should be overcome in order to have the regenerative dentistry as the important mean that can treat the consequences of tooth-related diseases.
doi:10.1155/2012/856470
PMCID: PMC3359805  PMID: 22666253
4.  Expression of Clock Proteins in Developing Tooth 
Gene expression patterns : GEP  2010;11(3-4):202-206.
Morphological and functional changes during ameloblast and odontoblast differentiation suggest that enamel and dentin formation is under circadian control. Circadian rhythms are endogenous self-sustained oscillations with periods of 24 hours that control diverse physiological and metabolic processes. Mammalian clock genes play a key role in synchronizing circadian functions in many organs. However, close to nothing is known on clock genes expression during tooth development. In this work, we investigated the expression of four clock genes during tooth development. Our results showed that circadian clock genes Bmal1, clock, per1, and per2 mRNAs were detected in teeth by RT-PCR. Immunohistochemistry showed that clock protein expression was first detected in teeth at the bell stage (E17), being expressed in EOE and dental papilla cells. At post-natal day four (PN4), all four clock proteins continued to be expressed in teeth but with different intensities, being strongly expressed within the nucleus of ameloblasts and odontoblasts and down-regulated in dental pulp cells. Interestingly, at PN21 incisor, expression of clock proteins was down-regulated in odontoblasts of the crown-analogue side but expression was persisting in root-analogue side odontoblasts. In contrast, both crown and root odontoblasts were strongly stained for all four clock proteins in first molars at PN21. Within the periodontal ligament (PDL) space, epithelial rests of Malassez (ERM) showed the strongest expression among other PDL cells. Our data suggests that clock genes might be involved in the regulation of ameloblast and odontoblast functions, such as enamel and dentin protein secretion and matrix mineralization.
doi:10.1016/j.gep.2010.12.002
PMCID: PMC3073654  PMID: 21156215
Clock genes; Tooth development; Bmal1; Clock; Per1; Per2; expression pattern; immunohistochemistry
5.  Regulation of Dental Enamel Shape and Hardness 
Journal of dental research  2010;89(10):1024-1038.
Epithelial-mesenchymal interactions guide tooth development through its early stages and establish the morphology of the dentin surface upon which enamel will be deposited. Starting with the onset of amelogenesis beneath the future cusp tip, the shape of the enamel layer covering the crown is determined by five growth parameters. Appositional growth occurs at a mineralization front along the ameloblast distal membrane in which amorphous calcium phosphate (ACP) ribbons form and lengthen. The ACP ribbons convert to calcium hydroxyapatite as the ribbons elongate. Appositional growth involves a secretory cycle that leaves an imprint of incremental lines. A potentially important function of enamel proteins is to ensure alignment of successive mineral increments on the tips of enamel ribbons deposited in the previous cycle so the crystallites lengthen with each cycle. Enamel crystallites harden in a maturation process that involves mineral deposition on the sides of existing crystallites until they interlock with adjacent crystallites. Neutralization of acidity generated by hydroxyapatite formation is a key part of the mechanism. Here we review the growth parameters that determine the shape of the enamel crown as well as the mechanisms of enamel appositional growth and maturation.
doi:10.1177/0022034510375829
PMCID: PMC3086535  PMID: 20675598
appositional growth; amelogenin; enamelin; ameloblastin; tooth
6.  Identifying Promoter Elements Necessary for Enamelin Tissue-Specific Expression 
Cells, tissues, organs  2008;189(1-4):98-104.
Enamel development requires the strictly regulated spatiotemporal expression of genes encoding enamel matrix proteins. The mechanisms orchestrating the initiation and termination of gene transcription at each specific stage of amelogenesis are unknown. In this study, we identify cis-regulatory regions necessary for normal enamelin (Enam) expression. Sequence analysis of the Enam promoter 5′-noncoding region identified potentially important cis-regulatory elements located within 5.2 kb upstream of the Enam translation initiation site. DNA constructs containing 5.2 or 3.9 kb upstream of the Enam translation initiation site were linked to an LacZ reporter gene and used to generate transgenic mice. The 3.9-kb Enam-LacZ transgenic lines showed no expression in ameloblasts, but ectopic LacZ staining was detected in osteoblasts. In contrast, the 5.2-kb Enam-LacZ construct was sufficient to mimic the endogenous Enam ameloblast-specific expression pattern. Our study provides new insights into the molecular control of Enam cell- and stage-specific expression.
doi:10.1159/000151429
PMCID: PMC2754408  PMID: 18703866
Enam; cis-regulatory elements; Ameloblasts; Enamel proteins; Osteoblasts; Tissue-specific expression
7.  Distal cis-regulatory elements are required for tissue-specific expression of enamelin (Enam) 
European journal of oral sciences  2008;116(2):113-123.
Enamel formation is orchestrated by the sequential expression of genes encoding enamel matrix proteins; however, the mechanisms sustaining the spatio–temporal order of gene transcription during amelogenesis are poorly understood. The aim of this study was to characterize the cis-regulatory sequences necessary for normal expression of enamelin (Enam). Several enamelin transcription regulatory regions, showing high sequence homology among species, were identified. DNA constructs containing 5.2 or 3.9 kb regions upstream of the enamelin translation initiation site were linked to a LacZ reporter and used to generate transgenic mice. Only the 5.2-Enam–LacZ construct was sufficient to recapitulate the endogenous pattern of enamelin tooth-specific expression. The 3.9-Enam–LacZ transgenic lines showed no expression in dental cells, but ectopic β-galactosidase activity was detected in osteoblasts. Potential transcription factor-binding sites were identified that may be important in controlling enamelin basal promoter activity and in conferring enamelin tissue-specific expression. Our study provides new insights into regulatory mechanisms governing enamelin expression.
doi:10.1111/j.1600-0722.2007.00519.x
PMCID: PMC2701970  PMID: 18353004
ameloblasts; enamel proteins; enamelin; osteoblasts; tissue-specific expression
8.  Functions of KLK4 and MMP-20 in dental enamel formation 
Biological chemistry  2008;389(6):695-700.
Two proteases are secreted into the enamel matrix of developing teeth. The early protease is enamelysin (MMP-20). The late protease is kallikrein 4 (KLK4). Mutations in MMP20 and KLK4 both cause autosomal recessive amelogenesis imperfecta, a condition featuring soft, porous enamel containing residual protein. MMP-20 is secreted along with enamel proteins by secretory stage ameloblasts. Enamel protein cleavage products accumulate in the space between the crystal ribbons, helping to support them. MMP-20 steadily cleaves accumulated enamel proteins, so their concentration decreases with depth. Kallikrein 4 is secreted by transition and maturation stage ameloblasts. KLK4 aggressively degrades the retained organic matrix following the termination of enamel protein secretion. The principle functions of MMP-20 and KLK4 in dental enamel formation are to facilitate the orderly replacement of organic matrix with mineral, generating an enamel layer that is harder, less porous, and unstained by retained enamel proteins.
doi:10.1515/BC.2008.080
PMCID: PMC2688471  PMID: 18627287
amelogenesis imperfecta; EMSP1; enamelysin; kallikrein; matrix metalloproteinase; tooth enamel
9.  Identifying Promoter Elements Necessary for Enamelin Tissue-Specific Expression 
Cells, Tissues, Organs  2008;189(1-4):98-104.
Enamel development requires the strictly regulated spatiotemporal expression of genes encoding enamel matrix proteins. The mechanisms orchestrating the initiation and termination of gene transcription at each specific stage of amelogenesis are unknown. In this study, we identify cis- regulatory regions necessary for normal enamelin (Enam) expression. Sequence analysis of the Enam promoter 5′-noncoding region identified potentially important cis-regulatory elements located within 5.2 kb upstream of the Enam translation initiation site. DNA constructs containing 5.2 or 3.9 kb upstream of the Enam translation initiation site were linked to an LacZ reporter gene and used to generate transgenic mice. The 3.9-kb Enam-LacZ transgenic lines showed no expression in ameloblasts, but ectopic LacZ staining was detected in osteoblasts. In contrast, the 5.2-kb Enam-LacZ construct was sufficient to mimic the endogenous Enam ameloblast-specific expression pattern. Our study provides new insights into the molecular control of Enam cell- and stage-specific expression.
doi:10.1159/000151429
PMCID: PMC2754408  PMID: 18703866
Enam; cis-regulatory elements; Ameloblasts; Enamel proteins; Osteoblasts; Tissue-specific expression

Results 1-9 (9)