The Dmp-1 Gene is Essential for Normal Post-natal Tooth Development

Objectives: Dentin matrix protein-1 (Dmp-1) has been postulated to play a role in dentinogenesis, cell attachment and mineralization, but the in vivo function of this molecule is unknown. In order to better understand the functions of this molecule we have utilized in vivo loss-of-function approach. Methods: A lacZ neo cassette was used to replace Dmp1 exon 6, which contains ~80% of the coding region. The Dmp1 null genotype was verified by Southern blot and PCR, and the phenotype was confirmed by a non-invasive technique of x-ray of the tail vertebrae for identification of the null phenotype. Vertebrae in the Dmp1 null mice are smaller and less mineralized than wild-type mice. X-gal staining was used to determine Dmp-1 expression during tooth development. Histology, electron microscopy, micro-radiography, Raman microspectroscopy, in situ hybridization and Piximus bone mineral densitometry were used to examine teeth and surrounding bone in Dmp1 null mice. Results: Newborn Dmp-1 null mice appear normal by both x-ray and by histology. However, by 3 weeks, an abnormal tooth phenotype starts to become evident in Dmp-1 null mice, which is summarized as follows: 1) reduced mineralization of both dentin and enamel; 2) dramatic expansion of the predentin region concurrent with reduction of dentin thickness; 3) a remarkable decrease of mineral in the peritubular dentin where the matrix is poorly organized; and 4) absence of the third molar among ~10% of the Dmp1 null mice while the other abnormalities show 100% penetrance. In addition, we for the first time demonstrate that Dmp1 is expressed in pulp cells during development. Conclusions: The Dmp1 gene is critical for postnatal tooth morphogenesis (growth and development) and mineralization, and may be a candidate gene for molar tooth agenesis. This work is supported by NIH-NIDCR grants DE00455 & DE13480 (JQF), DE13221 (MM), DE12487 (PS), and UM research Board.