title: Nucleus-targeted Dmp1 transgene fails to rescue dental defects in Dmp1 null mice.
abstract: Dentin matrix protein 1 (DMP1) is essential to odontogenesis. Its mutations in human subjects lead to dental problems such as dental deformities, hypomineralization and periodontal impairment. Primarily, DMP1 is considered as an extracellular matrix protein that promotes hydroxyapatite formation and activates intracellular signaling pathway via interacting with αvβ3 integrin. Recent in vitro studies suggested that DMP1 might also act as a transcription factor. In this study, we examined whether full-length DMP1 could function as a transcription factor in the nucleus and regulate odontogenesis in vivo. We first demonstrated that a patient with the DMP1 M1V mutation, which presumably causes a loss of the secretory DMP1 but does not affect the nuclear translocation of DMP1, shows a typical rachitic tooth defect. Furthermore, we generated transgenic mice expressing (NLS)DMP1, in which the endoplasmic reticulum (ER) entry signal sequence of DMP1 was replaced by a nuclear localization signal (NLS) sequence, under the control of a 3.6 kb rat type I collagen promoter plus a 1.6 kb intron 1. We then crossbred the (NLS)DMP1 transgenic mice with Dmp1 null mice to express the (NLS)DMP1 in Dmp1-deficient genetic background. Although immunohistochemistry demonstrated that (NLS)DMP1 was localized in the nuclei of the preodontoblasts and odontoblasts, the histological, morphological and biochemical analyses showed that it failed to rescue the dental and periodontal defects as well as the delayed tooth eruption in Dmp1 null mice. These data suggest that the full-length DMP1 plays no apparent role in the nucleus during odontogenesis.
authors.affiliation: 1] Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas, USA [2] The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine, Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: Shu-Xian
authors.initials: SX
authors.lastname: Lin
authors.affiliation: Laboratory of Oral Biomedical Science and Translational Medicine, Department of Endodontics, School of Stomatology, Tongji University, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, Columbia University, New York, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Yan
authors.affiliation: Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada.
authors.forename: Leanne
authors.initials: L
authors.lastname: Ward
authors.affiliation: Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas, USA.
authors.forename: Yong-Bo
authors.initials: YB
authors.lastname: Lu
authors.affiliation: Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas, USA.
authors.forename: Jian-Quan
authors.initials: JQ
authors.lastname: Feng
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000235:genetics*; D018387:Codon, Initiator / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D004721:Endoplasmic Reticulum / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D053098:Familial Hypophosphatemic Rickets / Q000235:genetics; D018390:Gene Targeting / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D008715:Methionine / Q000235:genetics; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009804:Odontoblasts / Q000166:cytology; D009805:Odontogenesis / Q000235:genetics; D010510:Periodontal Diseases / Q000235:genetics; D010513:Periodontal Ligament / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D014071:Tooth Abnormalities / Q000235:genetics*; D014078:Tooth Eruption / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D019076:Transgenes / Q000235:genetics*; D014633:Valine / Q000235:genetics; D055815:Young Adult
chemical_list: D018387:Codon, Initiator; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C513309:DMP1 protein, human; C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D008715:Methionine; D014633:Valine
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