Research Project
10440858
Title Genetic Regulatory Network in Craniofacial Development Abstract This proposal continues our efforts to decipher the skeletogenic signaling network underlying craniofacial development and disease. The craniofacial skeleton consists of viscerocranium and neurocranium, which is subdivided into the calvarium and chondrocranium. During development of the calvarium, cranial sutures serve as the growth center for skeletogenesis. Defects in suture morphogenesis resulting in premature closure cause craniosynostosis, a devastating childhood disease affecting 1 in ~2,500 individuals. Although human genetic analyses have identified genes associated with the pathogenesis, little is known about the regulation of suture closure essential for development of a healthy skull. In the previously proposed investigation, we have elucidated the mechanisms by which Axin2 regulates suture morphogenesis through modulations of Wnt and downstream signaling pathways. The crosstalk of BMP and FGF signaling plays a pivotal role in Wnt-mediated craniofacial bone development. Furthermore, skeletal stem cells residing in the suture mesenchyme have been successfully identified and isolated in our laboratory. This suture stem cell (SuSC) population is responsible for calvarial development in infants as well as homeostatic maintenance in adults. Upon injury, the dormant SuSCs respond quickly and contribute directly to bone repair in a cell autonomous fashion. In vivo clonal analysis demonstrates calvarial bone regeneration at a single cell level. Implantation of SuSCs to an injured site shows not only long-term survival but also facilitation of bone healing via direct engraftments in which the implanted stem cells give rise to osteogenic cell types in replacement of the damaged tissue. The newly discovered SuSCs thus provides an outstanding opportunity to gain novel insights into etiology of craniosynostosis. In this proposal, we continue our in-depth evaluations of SuSCs by examining their regulation essential for healthy development and homeostasis of the calvarium. We will concentrate on elucidation of molecular and cellular mechanisms underlying craniosynostosis caused by dysregulation of SuSCs.
