Abstract
Development of specialized cells and structures in the heart is regulated by spatially -restricted molecular pathways. Disruptions in these pathways can cause severe congenital cardiac malformations or functional defects. To better understand these pathways and how they regulate cardiac development we used tomo-seq, combining high-throughput RNA-sequencing with tissue-sectioning, to establish a genome-wide expression dataset with high spatial resolution for the developing zebrafish heart. Analysis of the dataset revealed over 1100 genes differentially expressed in sub-compartments. Pacemaker cells in the sinoatrial region induce heart contractions, but little is known about the mechanisms underlying their development. Using our transcriptome map, we identified spatially restricted Wnt/β-catenin signaling activity in pacemaker cells, which was controlled by Islet-1 activity. Moreover, Wnt/β-catenin signaling controls heart rate by regulating pacemaker cellular response to parasympathetic stimuli. Thus, this high-resolution transcriptome map incorporating all cell types in the embryonic heart can expose spatially restricted molecular pathways critical for specific cardiac functions.
Highlights
The vertebrate heart exerts regular contractions to circulate nutrients and oxygen
At 2 days post-fertilization (2 dpf), the zebrafish heart has developed into a looped structure with a recognizable atrium and ventricle that is able to sustain blood circulation in the larvae
Our results reveal a new role for Wnt/b-catenin signaling in the autonomic control of heart rate by regulating the response of pacemaker cells to parasympathetic stimuli (Figure 6G)
Summary
The vertebrate heart exerts regular contractions to circulate nutrients and oxygen. Cardiomyocyte contraction is caused by an action potential generated by cardiac pacemaker cells: spontaneous, rhythmic membrane depolarization of the pacemaker cells enables them to trigger the neighboring working myocardium to contract. Congenital malformations, aging, or somatic gene defects may cause pacemaker tissue dysfunction, resulting in severely disabling and potentially lethal bradycardia (inappropriately low heart rates) (Dobrzynski et al, 2007; Wolf and Berul, 2006) These conditions can be treated by implantation of an electronic pacemaker. Pacemaker cells are situated within, and coupled to, the surrounding cardiomyocytes, they retain a primitive myocardial identity (Bakker et al, 2010) This is established during cardiac development, when a myocardial progenitor cell population (Shox2+/Tbx18+/Isl1+/Nkx2.5-) becomes spatially restricted to the region connecting the sinus venosus to the atria (sinoatrial region). Functional analysis demonstrated that Wnt/ b-catenin signaling acts downstream of Isl to establish parasympathetic control of heart rate Together these results reveal a genetic pathway regulating autonomic control of pacemaker activity
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