title: Neural crest deletion of Dlx3 leads to major dentin defects through down-regulation of Dspp.
abstract: During development, Dlx3 is expressed in ectodermal appendages such as hair and teeth. Thus far, the evidence that Dlx3 plays a crucial role in tooth development comes from reports showing that autosomal dominant mutations in DLX3 result in severe enamel and dentin defects leading to abscesses and infections. However, the normal function of DLX3 in odontogenesis remains unknown. Here, we use a mouse model to demonstrate that the absence of Dlx3 in the neural crest results in major impairment of odontoblast differentiation and dentin production. Mutant mice develop brittle teeth with hypoplastic dentin and molars with an enlarged pulp chamber and underdeveloped roots. Using this mouse model, we found that dentin sialophosphoprotein (Dspp), a major component of the dentin matrix, is strongly down-regulated in odontoblasts lacking Dlx3. Using ChIP-seq, we further demonstrate the direct binding of Dlx3 to the Dspp promoter in vivo. Luciferase reporter assays determined that Dlx3 positively regulates Dspp expression. This establishes a regulatory pathway where the transcription factor Dlx3 is essential in dentin formation by directly regulating a crucial matrix protein.
authors.affiliation: Developmental Skin Biology Section, NIAMS, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Duverger
authors.forename: Angela
authors.initials: A
authors.lastname: Zah
authors.forename: Juliane
authors.initials: J
authors.lastname: Isaac
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Sun
authors.forename: Anne K
authors.initials: AK
authors.lastname: Bartels
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.forename: Ariane
authors.initials: A
authors.lastname: Berdal
authors.forename: Joonsung
authors.initials: J
authors.lastname: Hwang
authors.forename: Maria I
authors.initials: MI
authors.lastname: Morasso
mesh_terms: D000565:Ameloblasts / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D003743:Dental Enamel / Q000254:growth & development / Q000378:metabolism; D003804:Dentin / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D003805:Dentin Dysplasia / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008334:Mandible / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009432:Neural Crest / Q000378:metabolism*; D009804:Odontoblasts / Q000378:metabolism / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012795:Sialoglycoproteins / Q000235:genetics* / Q000378:metabolism; D014070:Tooth / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000099311:Dentin Sialophosphoprotein
chemical_list: D016326:Extracellular Matrix Proteins; D018398:Homeodomain Proteins; D049410:Luciferases, Renilla; D010750:Phosphoproteins; D012795:Sialoglycoproteins; D014157:Transcription Factors; D000099311:Dentin Sialophosphoprotein; C088334:Distal-less homeobox proteins