Mechanisms of boundary formation and septal morphogenesis at the interface between heart fields – HEARTBOUND

Congenital heart defects affect 1% of live births and have a major impact on mortality and morbidity. The most frequent anomalies affect essential barriers known as septa that separate pulmonary and systemic blood flow within the heart. Despite this clinical imperative, the mechanisms of septum morphogenesis are poorly understood. Insights have come from the realisation that cardiac septa arise at the boundary between early differentiating myocardium of the first heart field (FHF) and cells derived from the second heart field (SHF). New evidence reveals that transient coexpression of FHF and SHF regulators, followed by downregulation of SHF genes, precisely defines the sites of both atrial and ventricular septa. These findings indicate that the heart field interface is a boundary organiser that orchestrates cardiac septation. However, downstream effector genes driving boundary formation and initiating septal morphogenesis have yet to be identified. The overall objective of our project is to uncover how cells at the heart field interface establish a boundary and direct septum morphogenesis. Using in vivo mouse genetic lineage and functional analyses, quantitative imaging, spatial transcriptomics, together with in vitro embryo and gastruloid culture, we will dissect the genetic and cellular events regulating 1) boundary formation at the heart field interface and 2) morphogenesis of the muscular interventricular septum. Our experimental approach builds on new findings that dynamic changes in progenitor cell transcription, including downregulation of Hox gene expression, demarcate septal primordia along a common heart field boundary and that retinoic acid signaling is required for morphogenesis of the muscular ventricular septum, implicating a novel zipper mechanism initiating at the heart field interface. Our results will provide fundamental insights into mechanisms of organogenesis and a new paradigm for understanding the origins of congenital heart defects.