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Genomic and physiological analyses of the zebrafish atrioventricular canal reveal molecular building blocks of the secondary pacemaker region

ABSTRACT: The atrioventricular canal (AVC) is the site where key structures responsible for functional division between heart regions are established, most importantly, the atrioventricular (AV) conduction system and cardiac valves. To elucidate the mechanism underlying AVC development and function, we utilized transgenic zebrafish line sqet31Et expressing EGFP in the AVC to isolate this cell population and profile its transcriptome at 48 and 72 hpf. The zebrafish AVC transcriptome exhibits hallmarks of mammalian AV node, including the expression of genes implicated in its development and those encoding connexins forming low conductance gap junctions. Transcriptome analysis uncovered protein-coding and noncoding transcripts enriched in AVC, which have not been previously associated with this structure, as well as dynamic expression of epithelial-to-mesenchymal transition markers and components of TGF-β, Notch, and Wnt signaling pathways likely reflecting ongoing AVC and valve development. Using transgenic line Tg(myl7:mermaid) encoding voltage-sensitive fluorescent protein, we show that abolishing the pacemaker-containing sinoatrial ring (SAR) through Isl1 loss of function resulted in spontaneous activation in the AVC region, suggesting that it possesses inherent automaticity although insufficient to replace the SAR. The SAR and AVC transcriptomes express partially overlapping species of ion channels and gap junction proteins, reflecting their distinct roles. Besides identifying conserved aspects between zebrafish and mammalian conduction systems, our results established molecular hallmarks of the developing AVC which underlies its role in structural and electrophysiological separation between heart chambers. This data constitutes a valuable resource for studying AVC development and function, and identification of novel candidate genes implicated in these processes.

ORGANISM(S): Danio rerio

PROVIDER: GSE160107 | GEO | 2021/09/24

REPOSITORIES: GEO

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Project description:Rationale: A critical step in heart development is the coordinated formation of nodal myocardium and cushion tissue from the atrioventricular canal (AVC). After its specification, the myocardium of the AVC aligns the chambers, forms the AV node, and induces the formation of the mesenchymal AV cushions, primordia of valves and septa, while it resists working myocardial differentiation. Objective: To assess what roles Tbx2 and Tbx3, two closely related T-box transcription factors expressed in the AVC, play in these processes. Methods and Results: We analyzed mice ectopically expressing Tbx3 in the atrial myocardium by genome-wide microarray and expression analysis. We found a prominent role for Tbx3 in defining the nodal phenotype by repressing working myocardial genes (sarcomeric, mitochondrial, fast conduction) and cell proliferation regulators, and in inducing node-associated genes. Moreover, there was a striking induction of genes associated with endocardial cushions and mesenchyme. Using gain-of-function models, we found that in the developing heart both Tbx2 and Tbx3 induce ectopic Bmp2 and Tgfb2 expression and endocardial cushion formation. Analysis of compound Tbx2/Tbx3 mutant embryos revealed that upon loss of more than two functional alleles, expansion of the AV myocardium does not occur and AV cushions fail to form. Conclusions: Tbx2 and Tbx3 locally stimulate development of the AVC myocardium, induce the AV nodal phenotype therein and trigger AV cushion formation from the overlying AV endocardium, providing a mechanism for the colocalization and coordination of these two important processes in heart development. Nppa-Cre4 (Cre4) mice were crossed with CT mice to obtain efficient activation of Tbx3 in atria of double transgenic Cre4-CT mice, as previously described (Hoogaars et al., 2007). To investigate the gene expression profile of atria of Cre4-CT mice, we performed whole genome microarray analysis using Sentrix Mouse-6 oligonucleotide beadchips. We compared the atrial gene expression profiles of six male double transgenic Cre4-CT mice and six male Cre4 control mice.

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Genomic and physiological analyses of the zebrafish atrioventricular canal reveal molecular building blocks of the secondary pacemaker region

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