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

TitleGenomic and physiological analyses of the zebrafish atrioventricular canal reveal molecular building blocks of the secondary pacemaker region.
Publication TypeJournal Article
Year of Publication2021
AuthorsNahia, KAbu, Migdał, M, T Quinn, A, Poon, K-L, Łapiński, M, Sulej, A, Liu, J, Mondal, SS, Pawlak, M, Bugajski, Ł, Piwocka, K, Brand, T, Kohl, P, Korzh, V, Winata, C
JournalCell Mol Life Sci
Volume78
Issue19-20
Pagination6669-6687
Date Published2021 Oct
ISSN1420-9071
KeywordsAnimals, Animals, Genetically Modified, Embryo, Nonmammalian, Gene Expression Regulation, Developmental, Genome, Genomics, Heart Septal Defects, Heart Valves, Myocardium, Organogenesis, Pacemaker, Artificial, Wnt Signaling Pathway, Zebrafish, Zebrafish Proteins
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.

DOI10.1007/s00018-021-03939-y
Alternate JournalCell Mol Life Sci
Citation Key120
PubMed ID34557935
PubMed Central IDPMC8558220
Grant ListPOIR.04.04.00-00-1AF0/16-00/ / / fundacja na rzecz nauki polskiej /
OPUS Grant no. 2016/21/B/NZ3/00354 / / Narodowe Centrum Nauki /
The OPUS grant no. 2018/29/B/NZ2/01010L / / Narodowe Centrum Nauki /
OPUS Grant no. 2015/19/B/NZ2/01824 / / Narodowe Centrum Nauki /
DIAMENTOWY / / Narodowe Centrum Nauki /
RGPIN-2016-04879 / / The Natural Sciences and Engineering Research Council of Canada /
G-18-0022185 / / the Heart and Stroke Foundation of Canada /
MOP 3425620 / CAPMC / CIHR / Canada
PG/14/46/30911 / / The British Heart Foundation /
PG/14/83/31128 / / The British Heart Foundation /
422681845 / / deutsche forschungsgemeinschaft /
MOP 3425620 / CAPMC / CIHR / Canada