THE ROLE OF TRANSCRIPTION FACTOR MSX2 AND DLX5 IN CALVARIAL BONE AND SUTURE DEVELOPMENT

두개골 및 두개봉합부 초기발육과정에서의 전사조절인자인 Msx2와 Dlx5의 역할

  • Song, Min-Ho (Department of Pediatric Dentistry, College of Dentistry, Kyungpook National University) ;
  • Park, Mi-Hyun (Department of Oral Biochemistry, College of Dentistry, Kyungpook National University) ;
  • Nam, Soon-Hyeun (Department of Pediatric Dentistry, College of Dentistry, Kyungpook National University) ;
  • Kim, Young-Jin (Department of Pediatric Dentistry, College of Dentistry, Kyungpook National University) ;
  • Ryoo, Hyun-Mo (Department of Oral Biochemistry, College of Dentistry, Kyungpook National University) ;
  • Kim, Hyun-Jung (Department of Pediatric Dentistry, College of Dentistry, Kyungpook National University)
  • 송민호 (경북대학교 치과대학 소아치과학교실) ;
  • 박미현 (경북대학교 치과대학 생화학교실) ;
  • 남순현 (경북대학교 치과대학 소아치과학교실) ;
  • 김영진 (경북대학교 치과대학 소아치과학교실) ;
  • 류현모 (경북대학교 치과대학 생화학교실) ;
  • 김현정 (경북대학교 치과대학 소아치과학교실)
  • Published : 2003.08.30

Abstract

Craniosynostosis, known as a premature fusion of cranial sutures, is a developmental disorder characterized by precocious differentiation and mineralization of osteoblasts in the calvarial sutures. Recent genetic studies have demonstrated that mutation in the homeobox gene Msx2 causes Boston-type human craniosynostosis. Additionally, the phenotype of Dlx5 homozygote mutant mouse presents craniofacial abnormalities including a delayed ossification of calvarial bone. Furthermore transcription of osteocalcin, a mature osteoblast marker, is reciprocally regulated by the homeodomain proteins Msx2 and Dlx5. These facts suggest important roles of osteocalcin, Msx2 and Dlx5 genes in the calvarial bone growth and suture morphogenesis. To elucidate the function of these molecules in the early morphogenesis of mouse cranial sutures, we have first analyzed by in situ hybridization the expression of osteocalcin, Msx2 and Dlx5 genes in the developing parietal bone and sagittal suture of mouse calvaria during the embryonic (E15-E18) stage. Osteocalcin mRNA was found in the periosteum of parietal bones from E15, and gradually more highly expressed with aging. Msx2 mRNA was intensely expressed in the sutural mesenchyme, osteogenic fronts and mildly expressed in the dura mater during the embryonic stage. Dlx5 mRNA was intensely expressed osteogenic fronts and the periostem of parietal bones. To further examine the upstream signaling molecules of transcription factor Msx2 and Dlx5, we have done in vitro experiments in E15.5 mouse calvarial explants. Interestingly, implantation of BMP2-, BMP4-soaked beads onto the osteogenic fronts after 48 hours organ culture induced etopic expressions of Msx2 and Dlx5 genes. On the other hand, overexpression of $TGF{\beta}1$, GDF-6, -7, FGF-2, -4 and Shh did not induce the expression of Msx2 and Dlx5. Taken together. these data indicate that transcription factor Msx2 and Dlx5 play critical roles in the calvarial bone and suture development, and that BMP siganling is involved in the osteogenesis of calvarial bones and the maintenance of cranial sutures through regulating these two transcriotpn factors. Furthermore, different expression patterns between Msx2 and Dlx5 suggest their specific functions in the osteoblast differentiation.