Fig. 2: Progressive loss of pacemaker-associated gene expression in the developing delB SAN. | Nature Communications

Fig. 2: Progressive loss of pacemaker-associated gene expression in the developing delB SAN.

From: PITX2 dosage-dependent changes in pacemaker cell state underlie sinus node dysfunction and atrial arrhythmias

Fig. 2

a ISL1 is normally expressed in PCs throughout the SAN (outlined) at E12.5 (n = 5). Loss of ISL1 expression was detected as early as E12.5 in the delB/delB (n = 5) SAN (arrows). The expression domain of downstream functional markers HCN4 (pacemaker marker) and CX40 (working atrial myocardium marker) remain unchanged (wild-type, n = 5; delB/delB, n = 4). Scale is 100 μm. b Immunostainings show progressive loss of ISL1 and HCN4 (wild-type, n = 2; delB/delB, n = 3 alongside activation of NKX2-5 and CX40 expression (arrows) in the E14.5 SAN domain (outlined, wild-type, n = 2; delB/delB, n = 2). Scale is 100 μm. c Clusters of TNNI3+ cardiomyocytes in the SAN domain that have lost upstream (SHOX2) and downstream (HCN4) pacemaker gene expression by the end of gestation (E17.5, arrows) (wild-type, n = 3; delB/delB, n = 3). Scale is 100 μm. d Adjacent sections show co-localization of ISL1 and TBX3 expression with HCN4 in the wild-type SAN at E17.5 (n = 2). Clusters of TNNI3+ cells in the delB/delB SAN lack ISL1, TBX3 (n = 3) and HCN4 expression and express CX40 (panel, n = 4). Scale is 100 μm and panel scale is 10 μm. e Pacemaker-associated or working myocardium-associated gene expression is the product of a gene regulatory network. This gene regulatory network is progressively disrupted in the delB/delB SAN. Red arrows repress, and blue arrows drive. PC pacemaker cardiomyocyte, SAN sinus node, E embryonic day, RA right atrium, SCV superior caval vein, CM cardiomyocyte.

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