CBFA1, A CANDIDATE GENE FOR CLEIDOCRANIAL DYSPLASIA SYNDROME, IS ESSENTIAL FOR OSTEOBLAST DIFFERENTIATION AND BONE-DEVELOPMENT

We have generated Cbfa1-deficient mice. Homozygous mutants die of resp iratory failure shortly after birth. Analysis of their skeletons revea led an absence of osteoblasts and bane. Heterozygous mice showed speci fic skeletal abnormalities that are characteristic of the human herita ble skeletal disorder, cleidocranial dysplasia (CCD). These defects ar e also observed in a mouse Ccd mutant for this disease. The Cbfa1 gene was shown to be deleted in the Ccd mutation. Analysis of embryonic Cb fa1 expression using a lacZ reporter gene revealed strong expression a t sites of bone formation prior to the earliest stages of ossification . Thus, the Cbfa1 gene is essential for osteoblast differentiation and bone formation, and the Cbfa1 heterozygous mouse is a paradigm for a human skeletal disorder.