Ontogeny And Chromatin Signature of Cardiac Outflow Tract Lineage

DiGeorge syndrome is the most common chromosome microdeletion syndromewith diverse clinic presentations ranging from defects of craniofacial and cardiovascular structures toneurobehavioral, psychiatric and immunological defects. We have identified Six2 as a candidategenetic modifier that may impact on the phenotypic manifestation of the DiGeorge syndrome. Six2 isexpressed in most organs that are affected in DiGeorge syndrome implying that is broadly involved inthe disease process. However, the proposal here focuses exclusively on the involvement of Six2 insmooth muscle formation of the cardiac outflow tract, particularly the pulmonary trunk. We will test ahypothesis that the pulmonary trunk smooth muscle originates from a subpopulation of Six2-positiveprogenitors, and these progenitors are located in a spatiotemporally restricted domain of thepharyngeal apparatus. We further hypothesize that depending on location and timing, Six2-positiveprogenitors assume the lineage- and region-specific fates in the heart. Using a combination of aninducible genetic lineage tracing, lineage-specific cell labeling, and episcopic three-dimensional (3-D)imaging technologies, we will investigate the developmental history (fate commitment, differentiationand remodeling) of the pulmonary trunk smooth muscle. In addition, we will investigate candidateupstream signals to determine environment influence the fate of Six2-positive progenitors duringcardiac outflow tract development. Results from the proposed study are expected to gain insight intothe mechanism of vascular smooth muscle wall formation and may also improve our understanding ofthe disease process of DiGeorge syndrome.