Msx1/Bmp4 genetic pathway regulates bone formation via induction of mammalian alveolar Dlx5 and Cbfa1

In the developing mammalian tooth, the cranial neural crest derived dental mesenchyme consists of the dental papilla and dental follicle. The dental papilla gives rise to odontoblasts and dental pulp and the dental follicle gives rise to the periodontium, including the osteoblasts that contribute to the alveolar process. The alveolar process is a specialized intramembranous bone that forms the primary support structure for the dentition. The Msxl gene controls many aspects of craniofacial development, as evidenced by craniofacial abnormalities seen in Msxl(-/-) mice, including the arrest of tooth development and the absence of the alveolar bone. Previous studies demonstrated that ectopic expression of Bmp4, a downstream target of Msxl, in the Msxl(-/-) dental mesenchyme rescued alveolar bone formation. Here we confirm an early requirement of BMP activity for alveolar bone formation. We show that the expression of Cbfa1 and Dlx5, two genes encode transcription factors that are critical for bone differentiation, overlaps with that of Msxl and Bmp4 in the developing tooth and alveolar process. We have demonstrated that Dlx5 and Cbfal expression is down-regulated in Msxl(-/-) dental mesenchyme and that Msxl and BMP4 expression are unaltered in Cbfal(-/-) mice. These data place Dlx5 and Cbfal downstream from the Msxl/Bmp4 in the genetic pathway that regulates tooth development. Ectopic expression of Bmp4 in Msxl mutants restores the expression of Dlx5, but not Cbfal, in the dental mesenchyme, and rescues the expression of both Dlx5 and Cbfal in the developing alveolar bone. Therefore, the early expression of Cfbal in the dental mesenchyme appears dispensable for the development of the alveolar bone. Taken together with in vitro gene induction studies, our results demonstrate that BMP4 controls Dlx5 expression in dental mesenchyme, and functions upstream to both Dlx5 and Cbfal to regulate alveolar bone formation during tooth development. (C) 2003 Elsevier Ireland Ltd. All rights reserved.