title: Molecular and circadian controls of ameloblasts.
abstract: 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 the regulation of circadian rhythms. Our aim was to identify the potential links between daily rhythms and developmental controls of ameloblast differentiation. The effects of the transcription factors distal-less homeobox 3 (Dlx3) and runt-related transcription factor 2 (Runx2), and the clock gene nuclear receptor subfamily 1, group D, member 1 (Nr1d1), on secretory and maturation ameloblasts [using stage-specific markers amelogenin (Amelx), enamelin (Enam), and kallikrein-related peptidase 4 (Klk4)] were evaluated in the HAT-7 ameloblast cell line. Amelx and Enam steady-state mRNA expression levels were down-regulated in Runx2 over-expressing cells and up-regulated in Dlx3 over-expressing cells. In contrast, Klk4 mRNA 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. Multiscale 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.
authors.affiliation: Department of Orthodontics and Pediatric Medicine, Center for Computational Medicine and Bioinformatics, University of Michigan Schools of Dentistry and Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Athanassiou-Papaefthymiou
authors.forename: Doohak
authors.initials: D
authors.lastname: Kim
authors.forename: Lindsay
authors.initials: L
authors.lastname: Harbron
authors.forename: Silvana
authors.initials: S
authors.lastname: Papagerakis
authors.forename: Santiago
authors.initials: S
authors.lastname: Schnell
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Harada
authors.forename: Petros
authors.initials: P
authors.lastname: Papagerakis
mesh_terms: D000565:Ameloblasts / Q000166:cytology* / Q000502:physiology; D000566:Amelogenesis / Q000235:genetics*; D053523:Amelogenin / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002940:Circadian Rhythm / Q000235:genetics*; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D003746:Dental Enamel Proteins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics; D007610:Kallikreins / Q000096:biosynthesis / Q000235:genetics; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D053523:Amelogenin; C507201:Amelx protein, rat; D056925:Circadian Rhythm Signaling Peptides and Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D003746:Dental Enamel Proteins; C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; C498263:Nr1d1 protein, rat; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; C493717:Runx2 protein, rat; D014157:Transcription Factors; C038456:tuftelin; D056926:CLOCK Proteins; C538945:Clock protein, rat; D007610:Kallikreins; C120801:kallikrein 4