Abstract
Palate-derived growth factor receptor α (Pdgfrα) signaling has been reported to play important roles in the cardiac development. A previous study utilizing Pdgfrα conventional knockout mice reported hypoplasia of the sinus venous myocardium including the sinoatrial node (SAN) accompanied by increased expression of Nkx2.5. This mouse line embryos die by E11.5 due to embryonic lethality, rendering them difficult to investigate the details. To elucidate the underlying mechanism, in this study, we revisited this observation by generation of specific ablation of Pdgfrα in the SAN by Shox2-Cre at E9.5, using a Shox2-Cre;Pdgfrαflox/flox conditional mouse line. Surprisingly, we found that resultant homozygous mutant mice did not exhibit any malformation in SAN morphology as compared to their wild-type littermates. Further analysis revealed the normal cardiac function in adult mutant mice assessed by the record of heart rate and electrocardiogram and unaltered expression of Nkx2.5 in the E13.5 SAN of Pdgfrα conditional knockout mice. Our results unambiguously demonstrate that Pdgfrα is dispensable for SAN development after its fate commitment in mice.
Highlights
The mature sinoatrial node (SAN), composed of an Nkx2.5− head and an Nkx2.5+ sinoatrial junction or tail, is a group of specialized cells with obvious heterogeneity located on the dorsal wall of the right atrium close to the entrance of superior vena cava, functioning as the primary cardiac pacemaker that regulate the rhythm of the heartbeat by spontaneously producing electrical impulses (Christoffels et al, 2006; Yamamoto et al, 2006; Liu et al, 2007; Liang et al, 2013)
It has been reported that Palate-derived growth factor receptor α (Pdgfrα) is expressed as early as E7.5 in several cardiac progenitor tissues including SAN during early heart development (Prall et al, 2007; Bax et al, 2010; Bloomekatz et al, 2017)
Since the SAN is a structurally heterogeneous tissue composed of a head and junction with distinct gene expression profile (Li et al, 2019), we examined the expression of Pdgfrα in both domains, respectively
Summary
The mature sinoatrial node (SAN), composed of an Nkx2.5− head and an Nkx2.5+ sinoatrial junction or tail, is a group of specialized cells with obvious heterogeneity located on the dorsal wall of the right atrium close to the entrance of superior vena cava, functioning as the primary cardiac pacemaker that regulate the rhythm of the heartbeat by spontaneously producing electrical impulses (Christoffels et al, 2006; Yamamoto et al, 2006; Liu et al, 2007; Liang et al, 2013). The first heartbeat is recorded in the left inflow tract region as early as embryonic day (E) 8.0-E8.5 in mice (Yi et al, 2012), the pace-making activity is localized to the right inflow (Dyer and Kirby, 2009; Csepe et al, 2015). These pacemaker cells will contribute to the definitive SAN and become morphologically discernible at E10.5 and form the comma-like structure with the SAN-like action potential configurations at E12.5 (Virágh and Challice, 1982). Mice lacking Nkx2.5 in the SAN junction adopt normal morphology but physiological dysfunction, indicating that Nkx2.5 is essential for SAN function but is dispensable for SAN morphogenesis (Li et al, 2019)
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