ABSTRACT
Mutations in GATA6 are associated with congenital heart disease, most notably conotruncal structural defects. However, how GATA6 regulates cardiac morphology during embryogenesis is undefined. We used knockout and conditional mutant zebrafish alleles to investigate the spatiotemporal role of gata6 during cardiogenesis. Loss of gata6 specifically impacts atrioventricular valve formation and recruitment of epicardium, with a prominent loss of arterial pole cardiac cells, including those of the ventricle and outflow tract. However, there are no obvious defects in cardiac progenitor cell specification, proliferation or death. Conditional loss of gata6 starting at 24 h is sufficient to disrupt the addition of late differentiating cardiomyocytes at the arterial pole, with decreased expression levels of anterior secondary heart field (SHF) markers spry4 and mef2cb. Conditional loss of gata6 in the endoderm is sufficient to phenocopy the straight knockout, resulting in a significant loss of ventricular and outflow tract tissue. Exposure to a Dusp6 inhibitor largely rescues the loss of ventricular cells in gata6−/− larvae. Thus, gata6 functions in endoderm are mediated by FGF signaling to regulate the addition of anterior SHF progenitor derivatives during heart formation.
Footnotes
Author contributions
Conceptualization: J.S., T.E.; Methodology: J.S.; Validation: J.S.; Formal analysis: J.S.; Investigation: J.S., I.T.; Resources: T.E.; Data curation: J.S.; Writing - original draft: J.S.; Writing - review & editing: T.E.; Supervision: T.E.; Project administration: T.E.; Funding acquisition: T.E.
Funding
This work was supported by a grant from the National Institutes of Health to T.E. (R35 HL135778) and by a contract from the New York State Department of Health (NYSTEM) to T.E. (C32558GG). Deposited in PMC for release after 12 months.
Data availability
All relevant data can be found within the article and its supplementary information.
