Molecular Mechanisms of Development
Mechanisms underlying the specification and morphogenesis of organ systems
We are interested in the mechanisms underlying the specification and morphogenesis of organ systems. Our primary model system is the Drosophila body wall muscles, where genetics, molecular biology, cell biology, bioinformatics, in vivo confocal imaging and biochemistry are used to identify and understand genes required for myogenesis.
Our work has focused on determining the extrinsic signals and intrinsic factors that orchestrate the specification of these founder cells (FC). Indeed, we find that the activity of and cross talk between Wnt, BMP, Notch and Ras signaling pathways are crucial for FC specification. The activity of these signaling pathways regulate the activity of key transcriptional regulators such as the bHLH protein Twist, which, in turn, controls muscle identity. How these key transcriptional regulators act together to coordinate the final size, shape and orientation of a muscle is under investigation.
We are also applying our knowledge of the specification process to uncover the genes and processes that create the final muscle morphology: we are asking, for example, how muscle cells “count”, that is, determine the correct number of fusion events and how muscles achieve their final shape and orientation. A number of screens in the lab, including classical genetic screens, yeast two hybrid and microarray analysis, have led to the isolation of novel genes that, when mutated, disrupt muscle morphology. We are characterizing these genes genetically and biochemically and will fit them into the known hierarchy that controls myogenesis. We are currently investigating the process of cell-cell fusion and have uncovered several new genes required for the myoblast fusion process.
Improved imaging approaches in both live and fixed embryos have revealed new aspects of myoblast behavior and myoblast arrangements. These approaches have identified the actual site of myoblast fusion and an actin structure, which marks this site. Moreover these analyses have given us an unprecedented view of myoblast arrangements and dynamics over time. We have also extended this investigation by examining myogenesis in primary myoblasts derived from Drosophila embryos.
Lastly, we are applying our knowledge of Drosophila myogenesis to other model systems, namely mouse and human. For example, to address whether the molecules and mechanisms involved in Drosophila myoblast fusion are conserved in mammalian myoblast fusion, we recently have begun to test our paradigm in a mouse satellite-derived C2C12 myoblasts. In addition, many of the genes studied in the lab have been implicated in cancer and/or muscle disease. We are now testing the role of some of these key regulators in cancer models.
Research Fellow Krista Dobi has been selected to receive the DeLill Nasser Career Development Travel Award for 2012 by the Genetics Society of America.
Cornell Graduate Student Kate Rochlin won an award for her oral presentation on the Identification of a Novel Splicing Factor is Required for Proper Myotendenous Junction Formation and Maintenance in Drosophila at the 32nd Annual Vincent du Vigneaud Memorial Symposium on April 17, 2012. She was also selected for a poster prize at the New England Society for Developmental Biology Meeting held on Friday, April 13, through Sunday, April 15 in Woods Hole, Massachusetts.
Cornell Graduate Student Victoria Schulman won an American Society for Cell Biology (ASCB) Travel Award and was selected to participate in the 2012 St. Jude National Graduate Student Symposium (NGSS).