Scoliosis is a common disorder, affecting one out of every twenty females. Some forms of scoliosis are congenital, resulting from disruptions in early spinal development. The spinal column is patterned during a cycling process called somitogenesis, and is the first musculoskeletal structure formed during development. Genes in the notch-signaling pathway regulates somitogenesis, and display oscillatory expression in synchrony with semite formation. Intriguingly, the early myogenic factor, Myf5, is expressed cyclically in semite formation, as well as during semite maturation. Maturation of somites involves differentiation into myotomal, chondrocyte, and dermal cell lineages. We hypothesize that oscillation of notch pathway genes is essential both for somitogenesis and the earliest steps of myogenesis. Somitogenesis is one of the few mammalian processes that exhibit oscillatory gene expression, and microarray approaches have been used to successfully identify cycling genes in other systems. By microarray analysis of DII3-mutant mouse embryos, we have already identified novel candidates downstream of notch signaling, and known myogenic factors such as Myodl. We propose to i.) Identify novel cycling genes in semite formation, by time series microarray and computational analysis, ii.) Use gene expression studies of mouse mutants on an isogenic genetic background, to identify cycling and early myogenesis genes, and iii.) Develop an in vitro human mesenchymal stem cell model to characterize gene candidates. We have a unique opportunity to use microarray technology to identify novel genes with oscillatory expression in somitogenesis. These findings will immediately advance genetic studies on the etiology of congenital scoliosis and the regulation of early musculoskeletal development. In addition, insights into myotomal differentiation may advance efforts to use mesenchymal stem cells for repair of diseased and damaged tissues.
