LINEAGE ASSOCIATIONS DURING HEART DEVELOPMENT

Adult cardiac pathologies are associated with misrelated embryonic programs hence understanding cardiac development is essential for both basic and translational research. In this study we investigate the roles of Hand1 in CNC during heart formation. We find that loss of Hand1 in CNC leads to coronary developmental defects. The coronary vasculature develops but is mis-patterned with wide areas of the heart devoid of large vessels. We show that vasculogenesis was unaffected but angiogenesis was defective in mutant embryos due to defective coronary ostia development. Study also confirmed that Ednra loss results in a thin myocardial wall but also made the unique observation that Ednrb null mice had a more severe thinning of myocardial wall compared to Ednra null mice. Ednrb is also expressed in the sympathetic ganglia of the developing embryo and its loss results in hypoplastic sympathetic ganglia. Sympathetic ganglia and their support cells are NCderived structures. By in situ analyses we discovered a loss of Hand2 in the sympathetic ganglia in the DKO. Hand2 is required for the expression of norepinephrine biosynthetic enzymes in the developing sympathetic nervous system (SNS). Norepinephrine activates the heart to contract and previous reports from our group show that a lack of norepinephrine synthesis leads to a thin myocardial wall phenotype. This could explain the thin wall myocardium seen in Ednrb null and DKO embryos.