Investigating left-right patterning of the heart

Summary The focus of the Smith group is to identify the genetic and cellular processes that regulate heart development. The heart develops by differentiating and integrating multiple tissue types via a specific sequence of events to generate the stereotypical structure of the organ. The fact that this structure is more or less identical between individuals demonstrates that a tightly controlled genetic program instructs this process. The lab is interested in identifying the genes in this program, determining how they function and uncovering the cellular processes they regulate. We use the zebrafish model for much of our discovery-based projects. The zebrafish is an excellent genetic model and the transparency of the embryos and availability of fluorescent transgenic reporter lines permits live imaging of organogenesis. For particularly important projects, we translate our discoveries to the mouse models to investigate evolutionary conservation. The long-term objective of the lab is to contribute to our knowledge of how to build a heart, gathering along the way information that will assist bioengineering efforts and help with diagnosis and treatment of genetic-based heart disease.

Project Details

The focus of the Smith group is to identify the genetic and cellular processes that regulate heart development. The heart develops by differentiating and integrating multiple tissue types via a specific sequence of events to generate the stereotypical structure of the organ. The fact that this structure is more or less identical between individuals demonstrates that a tightly controlled genetic program instructs this process. The lab is interested in identifying the genes in this program, determining how they function and uncovering the cellular processes they regulate.  We use the zebrafish model for much of our discovery-based projects. The zebrafish is an excellent genetic model and the transparency of the embryos and availability of fluorescent transgenic reporter lines permits live imaging of organogenesis. For particularly important projects, we translate our discoveries to the mouse models to investigate evolutionary conservation. The long-term objective of the lab is to contribute to our knowledge of how to build a heart, gathering along the way information that will assist bioengineering efforts and help with diagnosis and treatment of genetic-based heart disease.

The heart is an asymmetric organ. Not only is it positioned on the left side of the body but it possesses asymmetry intrinsic to the organ itself. The heart begins as a simple symmetrical tube and asymmetry is imposed as the heart twists and bends to form what is called the "looped heart". This asymmetric morphogenesis always occurs with left-right bias in the same direction and is, therefore, not a random occurrence but genetically hardwired. The lab has identified an early left-right asymmetry that precedes asymmetric looping of the heart and we believe is instructive to directional cardiac looping – i.e. how the overall shape on an organ is made. We have developed a number of transgenic models to perform detailed imaging on live zebrafish embryos and we have developed genetic and chemical tools to study how this process is perturbed and what the consequences are to organ development. Methods used in the project will include embryology (of zebrafish), drug and chemical treatments, genetic crosses, molecular techniques (such as DNA extraction, PCR, gel electrophoresis), phenotypic screening by bright-field and fluorescence microscopy, confocal microscopy, image analysis and data quantification.