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Nucleus-targeted Dmp1 transgene fails to rescue dental defects in Dmp1 null mice

International Journal of Oral Science 2014年第3期6卷 133-141页

作者： Shu-Xian Lin Qi Zhang Hua Zhang Kevin Yan leanne ward Yong-Bo Lu Jian-Quan Feng Department of Biomedical Sciences Texas A&M University Baylor College of Dentistry 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 Laboratory of Oral Biomedical Science and Translational Medicine Department of Endodontics School of Stomatology Tongji University Department of Biological Sciences Columbia University Children’s Hospital of Eastern Ontario University of Ottawa

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 avb3 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 DMP1M1 V 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 expressingNLSDMP1, 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 theNLSDMP1 transgenic mice with Dmp1 null mice to express the NLSDMP1 in Dmp1-deficient genetic background. Although immunohistochemistry demonstrated thatNLSDMP1 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.

关键词： autosomal recessive hypophosphatemic rickets dentin matrix protein 1 development odontoblast odontogenesis

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