REGULATION OF CRANIAL SUTURE MORPHOGENESIS

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A variety of congenital craniofacial anomalies arise as a consequence of defects in the process of suture morphogenesis, including agenesis, the failure to form sutures; premature synostosis; and dysostosis. To better understand, diagnose and treat these disorders, this project's long-term goal is elucidating the mechanisms governing suture formation, maintenance of patency, and function as a bone growth center. To achieve this goal four specific aims are proposed: 1) characterization of the tissue interactions of dura mater and periosteum with developing calvaria (bones and suture) critical to suture formation, patency and growth function; 2) characterization and identification of the factor(s) expressed by dura mater which are required for suture patency; 3) characterization of the local-acting factors and interacting molecules regulating proliferation and differentiation in the osteogenic cell populations of the peri-sutural tissues; and 4) test the effects of candidate factors and antagonists on patency and growth functions by injection into coronal sutures. The model for these studies is the developing coronal suture of the rat, which will be examined in a surgical transplant system, in serum free culture of calvaria, in isolated cell populations and in intact neonatal animals. The involvement of each associated tissue in the suture morphogenesis and function will be indicated by removing the tissue at various stages of development and evaluating the formation of sutures, maintenance of patency and bone growth. Employing in vitro measurement of sutural stenosis, cellular proliferation and osteogenic differentiation as bio- assays, factors involved will be fractionated and identified. A heparin- binding factor expressed by fetal dura mater will be characterized in depth, and if novel, cloned and sequenced. Identification of soluble factors influencing proliferation and differentiation of and expressed by each cell population will help elucidate which osteogenic cells produce the bone at the sutural margin and bridge the suture during synostosis. These studies may identify regulatory factors and signalling pathways critical to suture development and function, which when perturbed contribute to craniofacial pathology.