Deletion of the Dentin Matrix Protein (Dmp-1) Gene Results in Severe Craniofacial Defects during Post-natal Development

Objectives: Craniofacial morphogenesis (growth and development) and mineralization require precise spatial and temporal coordination of programs for cell growth, differentiation, migration, and fusion. If one of these programs is interrupted or perturbed, craniofacial disorders will occur. In a search for genes required for normal craniofacial development potentially linked to human craniofacial diseases, we have studied the effects of deleting Dmp1, an anionic phosphoprotein highly expressed in the skeleton, using an in vivo lacZ knock-in approach. Methods: A lacZ-neo cassette was used to replace Dmp-1 exon 6, which contains ~80% of the coding region. Histology, electron microscopy, micro-radiography, FTIR microspectroscopy and Piximus bone densitometry were used to characterize the craniofacial phenotype in Dmp1 null mice from neonates to one year of age. Results: Newborn Dmp-1 null mice appear normal by both x-ray and histology. Surprisingly, by 2-3 weeks after birth Dmp-1 deficient mice begin to display profound skeletal abnormalities. These include: 1) a biphasic change of ossification in the skull with an increase at 19 days followed by a decrease with age as compared to wild-type mice; 2) dramatic alterations in the shape and size of the calvariae, mandible, temporomandibular condyle and other regions of the craniofacial skeleton; 3) a delay in fusion of the sutures of the cranium; and 4) the alveolar bone is poorly organized and filled with large areas of primary osteoid, suggesting failure of woven bone to mature into a compact bone. Conclusions: Dmp1 is critical for craniofacial morphogenesis during postnatal development, and the Dmp-1 knockout mouse may be a useful model in the study of craniofacial disorders. This work is supported by NIH-NIDCR grants DE00455 and DE13480 (JQF), DE13221 (MM), and DE04141 (AB), and UM research Board.