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

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 NLSDMP1, 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 NLSDMP1 transgenic mice with Dmp1 null mice to express the NLSDMP1 in Dmp1-deficient genetic background. Although immunohistochemistry demonstrated that NLSDMP1 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. A protein involved in tooth mineralization, although found in the nucleus, does not seem to play a role there during tooth formation. Dentin matrix protein 1 (DMP1) is present both in the nucleus and in the cytoplasm of odontoblasts, cells that form part of the dental pulp. To examine DMP1's role during embryonic tooth development, a team led by Jian-Quan Feng of the Texas A&M University Baylor College of Dentistry, USA, bred transgenic mice that only express DMP in the nucleus. These mice displayed dental defects and delayed tooth eruption similar to the defects seen in mouse strains with no functional versions of DMP1 in the nucleus or the cytoplasm. A human patient with a DMP1 gene mutation that causes only nuclear protein localization also exhibited tooth abnormalities consistent with rickets.

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