title: Transcriptional repression of the Dspp gene leads to dentinogenesis imperfecta phenotype in Col1a1-Trps1 transgenic mice.
abstract: Dentinogenesis imperfecta (DGI) is a hereditary defect of dentin, a calcified tissue that is the most abundant component of teeth. Most commonly, DGI is manifested as a part of osteogenesis imperfecta (OI) or the phenotype is restricted to dental findings only. In the latter case, DGI is caused by mutations in the DSPP gene, which codes for dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). Although these two proteins together constitute the majority of noncollagenous proteins of the dentin, little is known about their transcriptional regulation. Here we demonstrate that mice overexpressing the Trps1 transcription factor (Col1a1-Trps1 mice) in dentin-producing cells, odontoblasts, present with severe defects of dentin formation that resemble DGI. Combined micro-computed tomography (µCT) and histological analyses revealed tooth fragility due to severe hypomineralization of dentin and a diminished dentin layer with irregular mineralization in Col1a1-Trps1 mice. Biochemical analyses of noncollagenous dentin matrix proteins demonstrated decreased levels of both DSP and DPP proteins in Col1a1-Trps1 mice. On the molecular level, we demonstrated that sustained high levels of Trps1 in odontoblasts lead to dramatic decrease of Dspp expression as a result of direct inhibition of the Dspp promoter by Trps1. During tooth development Trps1 is highly expressed in preodontoblasts, but in mature odontoblasts secreting matrix its expression significantly decreases, which suggests a Trps1 role in odontoblast development. In these studies we identified Trps1 as a potent inhibitor of Dspp expression and the subsequent mineralization of dentin. Thus, we provide novel insights into mechanisms of transcriptional dysregulation that leads to DGI.
authors.affiliation: Institute of Oral Health Research, Department of Oral and Maxillofacial Surgery, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA. dobrawan@uab.edu
authors.forename: Dobrawa
authors.initials: D
authors.lastname: Napierala
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
authors.forename: Izabela
authors.initials: I
authors.lastname: Maciejewska
authors.forename: Terry K
authors.initials: TK
authors.lastname: Bertin
authors.forename: Brian
authors.initials: B
authors.lastname: Dawson
authors.forename: Rena
authors.initials: R
authors.lastname: D'Souza
authors.forename: Chunlin
authors.initials: C
authors.lastname: Qin
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D003804:Dentin / Q000378:metabolism; D003811:Dentinogenesis Imperfecta / Q000235:genetics* / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D050980:GATA Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009804:Odontoblasts / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000099311:Dentin Sialophosphoprotein
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016326:Extracellular Matrix Proteins; D050980:GATA Transcription Factors; D010750:Phosphoproteins; D012097:Repressor Proteins; D012795:Sialoglycoproteins; D000099311:Dentin Sialophosphoprotein; C525953:Trps1 protein, mouse