Defining the Cellular Morphogenic Behaviors that Shape the Developing Heart

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PROJECT SUMMARY Congenital heart defects (CHDs) are among the most prevalent and devastating congenital disorders, occurring in nearly 1% of live births and creating live-changing complications for affected individuals. The origins of CHDs lie early in embryogenesis as the heart takes shape. Previous studies have demonstrated that the earliest cardiac progenitor cells are specified during gastrulation, and then migrate to the anterior of the embryo to form the transient cardiac crescent and subsequent linear heart tube. Thereafter, the heart tube undergoes right-ward looping to properly position the segments of the heart tube and produce the four-chambered adult heart. Although the gross morphological processes that facilitate heart development have been described, the specific cellular behaviors that drive these processes remain unknown. The primary objective of this proposed work is to precisely define the cellular morphogenic behaviors, and their genomic determinants, that shape the developing heart in order to better understand how CHDs arise when these behaviors are mis-regulated. This will be achieved through three specific aims: i) Defining the cellular morphogenic behaviors that underlie heart tube formation by conducting live imaging of cardiac progenitors during cardiogenesis in mouse embryos; ii) Determining the role of key cardiac transcription factors Tbx5 and Mef2c in heart tube morphogenesis by quantifying disrupted cellular behaviors en route to improper heart tube formation in mutant embryos; iii) Identifying the genomic determinants of heart tube morphogenesis by performing multiomic analysis of gene expression and chromatin accessibility for wild type, Tbx5-null, and Mef2c- null embryos. This postdoctoral training will be conducted under the supervision of Dr. Benoit Bruneau, a leader in the fields of cardiac biology and embryology, at Gladstone Institutes, a world-renowned research center with an outstanding commitment to the career development of its trainees. The Bruneau laboratory and the Gladstone core facilities will provide all the necessary resources and expertise required to enable successful completion of the proposed work. The combination of high-resolution live embryo imaging and single cell genomic analysis will identify both the physical processes that are required to build the heart, as well as the transcriptional programs that spatiotemporally regulate those cellular behaviors. This information will advance our understanding of mammalian cardiogenesis beyond the current single-gene paradigm, and will provide important insights to inform how CHDs arise during embryogenesis.