A GATA-6 gene heart-region-specific enhancer provides a novel means to mark and probe a discrete component of the mouse cardiac conduction system

Abstract

The transcriptional programs that specify the distinct components of the cardiac conduction system are poorly understood, in part due to a paucity of definitive molecular markers. In the present study we show that a cGATA-6 gene enhancer can be used to selectively express transgenes in the atrioventricular (AV) conduction system as it becomes manifest in the developing multichambered mouse heart. Furthermore, our analysis of staged cGATA-6/lacZ embryos revealed that the activity of this heart-region-specific enhancer can be traced back essentially to the outset of the cardiogenic program. We provide evidence that this enhancer reads medial/lateral and anterior/posterior positional information before the heart tube forms and we show that the activity of this enhancer becomes restricted at the heart looping stage to AV myocardial cells that induce endocardial cushion formation. We infer that a deeply-rooted heart-region-specific transcriptional program serves to coordinate AV valve placement and AV conduction system formation. Lastly, we show that cGATA-6/Cre mice can be used to delete floxed genes in the respective subsets of specialized heart cells.

MEF2C is required for the normal allocation of cells between the ventricular and sinoatrial precursors of the primary heart field

“…7L). The remaining positive cells were in the sinoatrial region from which they eventually contribute to the AVC and part of the atria during looping morphogenesis (data not shown) (Davis et al, 2001). The anterior crescent of the mutant fails to expand at 4 SP ( Fig.…”

“…Treatment with retinoic acid causes an anterior expansion of the inflow and a commensurate decrease in the outflow that is similar, but substantially more severe, to that caused by deleting mef2c (Xavier-Neto et al, 1999;Davis et al, 2001;Hochgreb et al, 2003). In addition to the morphological similarities, shared changes in gene expression are the reduced domain of the ventriclespecific mlc2v gene and the anterior expansion of the sinoatrial-enriched tbx5 gene (Xavier-Neto et al, 1999;Liberatore et al, 2000).…”

“…This reporter primarily marks the cells of the AVC during looping, but its expression extends a little beyond into the left ventricle and atria. Importantly, it marks precursors of these regions beginning at the onset of cardiogenesis (Davis et al, 2001). Thus, it provides a means to examine the boundary between the atrial and ventricular precursors in mef2c Ϫ/Ϫ embryos during tube formation.…”

“…Although suggestive, a more exact delineation of these precursor domains was derived from expression of the cGata6LacZ transgene. This transgene is remarkable in marking the distal, posterior aspects of the cardiac crescent that will give rise predominately to the AVC but also to immediately adjacent regions of the LV and atria (Davis et al, 2001). Because there was no distinction in cGata6LacZ expression between the wildtype and mutant until immediately prior to formation of the linear tube, it appears that the early steps in specifying these lineages are intact (Fig.…”

The TGFβ type II receptor plays a critical role in the endothelial cells during cardiac development

“…We, therefore, sought to determine the role of the Tgfbr2 receptor in this tissue using the cGata6-Cre mouse, which drives Cre expression from a Gata6 enhancer sequence in the AV canal myocardium from E8.5 (Davis et al, 2001). Using this Cre line, the BMP type I receptor, Alk3, has previously been shown to be important for the development of the cardiac valves and conduction tissues (Gaussin et al, 2002(Gaussin et al, , 2005.…”