GATA6 reporter gene reveals myocardial phenotypic heterogeneity that is related to variations in gap junction coupling

Abstract

This study examined transgenic mice whose expression of a β-galactosidase (lacZ) reporter is driven by a GATA6 gene enhancer. Previous investigations established that transcription of the transgene was associated with precardiac mesoderm and primary heart tube myocardium, which decreased progressively, so that its expression was no longer observed within ventricular myocardium by midgestation. Expression of this reporter in the adult was investigated for insights into myocyte homeostasis and cardiovascular biology. Morphometric analysis determined that <1% of myocytes, often found in small clusters, express this GATA6-associated reporter in the adult heart. LacZ expression was also found in the ascending aorta. Myocardial expression of the transgene was not associated with a proliferative phenotype or new myocyte formation, as lacZ-positive myocytes neither labeled with cell division markers nor following 5-bromodeoxyuridine pulse-chase experimentation. Despite exhibiting normal adherens junctions, these myocytes appeared to exhibit decreased connexin 43 gap junctions. Treatment with the gap junctional blocker heptanol both in vivo and in culture elevated myocardial β-galactosidase activity, suggesting that deficient gap junctional communication underlies expression of the transgenic reporter. LacZ expression within the myocardium was also enhanced in response to cryoinjury and isoproterenol-induced hypertrophy. These results reveal a previously uncharacterized phenotypic heterogeneity in the myocardium and suggest that decreased gap junctional coupling leads to induction of a signaling pathway that utilizes a unique GATA6 enhancer. Upregulation of lacZ reporter gene expression following cardiac injury indicates this transgenic mouse may serve as a model for examining the transition of the heart from healthy to pathological states.

Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot

“…GATA6 is an upstream transcriptional regulator of multiple genes expressed during embryogenesis and cardiac morphogenesis, including the genes that encode atrial natriuretic factor (ANF), brain natriuretic peptide, α-myosin heavy chain, β myosin heavy chain, and gap junction protein connexin-40 (52). Therefore, the functional characteristics of the GATA6 mutations may be delineated by assessing the transcriptional activity of the ANF promoter in cultured cells.…”

Prevalence and spectrum of GATA6 mutations associated with familial atrial fibrillation

“…Previous studies have demonstrated that GATA6 is an upstream regulator of some genes expressed during cardiac development, including β myosin heavy chain, atrial natriuretic peptide, and gap junction genes [6,12], and mutations in several target molecules have been linked to AF [5]. Therefore, mutated GATA6 probably confers susceptibility to AF by reducing expression of target genes.…”

A novel GATA6 mutation associated with congenital ventricular septal defect

“…Previous studies have revealed that GATA6 is an upstream transcriptional regulator of several genes expressed during cardiac development, including genes that encode atrial natriuretic peptide, brain natriuretic factor, gap junction protein, and β-myosin heavy chain (40). GATA6 may bind to downstream target DNA alone or together with other partners including NKX2-5, GATA4, GATA5 and TBX5, and the synergistic transcriptional activations mediated by these transcription factors have been substantiated (36,41,42).…”