Dorn T , Goedel A , Lam JT , Haas J , Tian Q , Herrmann F , Bundschu K , Dobreva G , Schiemann M , Dirschinger R , Guo Y , Kühl SJ , Sinnecker D , Lipp P , Laugwitz KL , Kühl M , Moretti A .

	Figure 1. Precocious overexpression of Nkx2–5 in mouse ESCs suppresses the cardiac program during early mesoderm development. (A): Generation of Nkx2–5OE ESCs by lentiviral‐mediated Nkx2–5 overexpression in the Isl1‐nlacZ knock‐in ESC line. An empty IRES‐eGFP vector was used to obtain the control GFP ESC line. (B): Western blot analysis of Nkx2–5 protein in undifferentiated parental Isl1‐nlacZ knock‐in, GFP, and Nkx2–5OE ESCs. β‐Actin is shown as a loading control. (C): LacZ reporter gene expression assessed by X‐Gal staining in EBs from GFP (top panels) and Nkx2–5OE (bottom panels) ESCs at days (d) 3, 4, and 5 of differentiation. Scale bars = 150 µm. (D): Quantification of β‐gal+ cells arising during EB differentiation of GFP (black diamonds) and Nkx2–5OE (gray circles) ESCs at indicated time points. Mean values ± SEM from three experiments; *, p < .05 and **, p < .01 versus GFP. (E): Quantitative reverse transcription polymerase chain reaction analysis of cardiac progenitor genes in GFP (black bars) and Nkx2–5OE (gray bars) differentiating EBs at the indicated time points. Data are mean ± SEM from three independent experiments; *, p < .05 and **, p < .01 versus GFP at the same time point. Abbreviations: EB, embryoid body; ESC, embryonic stem cell; FRT, flippase recognition target; GFP, green fluorescent protein; IRES, internal ribosome entry site; PGK, phosphoglycerate kinase; PPT, polypurine tract.
	Figure 2. Constitutive Nkx2–5 and Isl1 overexpression have opposing effects on the specification of Isl1+ cardiac progenitors in mouse ESCs. (A): Western blot analysis of Isl1 protein in undifferentiated parental Isl1‐nlacZ knock‐in, GFP, and Isl1OE ESCs. β‐Actin is shown as a loading control. (B): Quantification of β‐gal+ cells arising during EB differentiation of GFP (black diamonds) and Isl1OE (red squares) ESCs at indicated time points. For better visualization, the number of β‐gal+ cells per EB is shown at d4 as inset (GFP, black bar; Isl1OE, red bar). Mean values ± SEM from three experiments; *, p < .05 versus GFP. (C): Quantitative reverse transcription polymerase chain reaction analysis of cardiac progenitor genes in GFP (black bars) and Isl1OE (red bars) differentiating EBs at the indicated time points. Mean values ± SEM from three independent experiments; *, p < .01 versus GFP at the same time point. (D): Quantification of β‐gal+ cells arising during EB differentiation of GFP (black diamonds), Nkx2–5OE (gray circles), and Isl1OE (red squares) ESCs at indicated time points after mitomycin C (Mit C) treatment at day 3. Mean values ± SEM from three experiments; *p < .05 versus GFP. (E): Representative bright field images of flow cytometry‐sorted FDG− (left) and FDG+ (right) cells after X‐Gal staining; scale bars = 150 µm. (F): Quantitative RT‐PCR analysis of Isl1 transcript in FDG− (black bars) and FDG+ (blue bars) cells after flow cytometry purification from GFP, Nkx2–5OE, and Isl1OE 4‐day‐old EBs. Values are relative to GFP and presented as mean ± SEM from three independent experiments; *, p < .01 versus FDG– cells from the same ESC line. (G, H): Flow cytometry analysis for Ki67 (lower panels) and IgG control (upper panels) of FDG+ sorted cells from 5‐day‐old GFP, Nkx2–5OE, and Isl1OE EBs (G). Quantification of Ki67+ cells in GFP (black bar), Nkx2–5OE (gray bar), and Isl1OE (red bar) EBs. Mean values ± SEM from three experiments (H). Abbreviations: EB, embryoid body; ESC, embryonic stem cell; FSC, forward side scatter; GFP, green fluorescent protein.
	Figure 3. Nkx2–5 negatively regulates cardiac progenitor specification by direct inhibition of Isl1 transcription. (A): Expression levels of Isl1 downstream target genes in FDG+ cells sorted from GFP (black bars), Nkx2–5OE (gray bars), and Isl1OE (red bars) 4‐day‐old embryoid bodies (EBs). Values are relative to GFP and presented as mean ± SEM from three independent experiments; *, p < .05 and **, p < .01 versus GFP. (B): Genomic locus of Isl1 gene 10 kb upstream and 10 kb downstream of the coding sequence with predicted Nkx2–5 binding sites (5′‐TYAAGTG‐3′). The 3.9‐kb region at 4.3 kb upstream of the Isl1‐ATG contains three highly conserved Nkx2–5 binding sites, as shown in a cross‐species sequence comparison. (C): Bar graph of luciferase activity. A minimal‐promoter‐containing pgl4.24 vector is compared with the same vector containing the 3.9 kb DNA piece upstream of Isl1 highlighted in panel B. Experiments are performed in C3H 10T1/2 cells after cotransfection with an empty expression vector (basal) or with vectors encoding Nkx2–5 and GFP. Data are means ± SEM; **, p < .01; n = 8. (D): Electromobility shift assay using 27–29 bp labeled probes containing each Nkx2–5 binding site within the 3.9 kb region upstream of Isl1. A black arrow indicates the shifted band. Nuclear extract of HEK293T cells overexpressing Nkx2–5 is used to induce shifting. :10, nuclear extract diluted 1 to 10. Nonlabeled oligos and mutated nonlabeled oligos are used as competitors. Mutated, labeled oligos are used as negative control. Abbreviations: GFP, green fluorescent protein; RLU, relative light unit.
	Figure 4. Negative regulation of Isl1 by Nkx2–5 occurs during second heart field progenitor differentiation into cardiomyocytes in vivo. (A): Isl1‐Cre knock‐in mice (Isl1Cre/+) were crossed with mice carrying floxed Nkx2–5 alleles (Nkx2–5fl/fl) to generate tissue‐specific deletion of Nkx2–5. (B): Whole‐mount in situ analysis for expression of Nkx2–5 mRNA (dark blue) in Isl1‐Cre;Nkx2–5 mutants (Isl1Cre/+;Nkx2–5fl/fl, right panels) and somite‐matched littermate controls (Isl1+/+;Nkx2–5fl/fl, left panels) at ED9.5 (20–21 somite pairs). (C): Whole‐mount RNA in situ hybridization for Isl1 in ED9.0 embryos (16 somite pairs) from Isl1+/+;Nkx2–5fl/fl controls (left panels) and Isl1Cre/+;Nkx2–5fl/fl mutants (right panels). Arrows indicate persisting Isl1 expression in the forming ventricular and atrial regions of the mutant hearts. Images are representative of five embryos per genotype. (D): Representative images of transverse sections of control Isl1+/+;Nkx2–5fl/fl (left panels) and mutant Isl1Cre/+;Nkx2–5fl/fl (right panels) ED9.25 embryos (18–19 somite pairs) after immunofluorescence analysis of Isl1 (red) and cTnT (green) protein expression. Sections correspond to the position indicated by the lines drawn through the adjacent embryo view. Scale bars = 50 µm. Images are representative of three embryos per genotype. White bracket marks malformed RV/OFT in Nkx2–5 mutants. Abbreviations: A, atria; AVC, atrioventricular canal; LA, left atrium; LV, left ventricle; OFT, outflow tract; RV, right ventricle; SV, sinus venosus; V, ventricle.
	Figure 5. Constitutive overexpression of Isl1 does not prevent cardiac differentiation in mouse embryonic stem cells (ESCs) and in Xenopus laevis embryos. (A): Analysis of beating activity during EB differentiation of GFP (top) and Isl1OE (bottom) ESCs. Median values, first and third quartile as well as minimal and maximal values are given of five independent experiments; *, p < .005 versus GFP ESC line. (B): Representative images of 14‐day‐old EBs from GFP and Isl1OE ESCs after immunofluorescence staining for cTnT (red), indicating that Isl1 overexpression results in bigger myocyte clusters; scale bars = 100 µm. (C): Flow cytometry‐based quantification of cTnT+ cells at 14 days of EB differentiation of GFP and Isl1OE ESCs. Mean values ± SEM from eight independent experiments. (D): Immunofluorescence images of GFP and Isl1OE cardiomyocytes following staining with antibodies against Isl1 (red) and cTnT (green); nuclei (blue) are visualized by DAPI. Scale bars = 15 µm. (E): Beating frequency of contractile areas in GFP (black filled squares) and Isl1OE (black filled triangles) EBs at 14 days of differentiation. Mean values ± SEM, n = 170 for GFP and n = 150 for Isl1OE from six to seven independent experiments. (F): GFP expression after unilateral and bilateral coinjection of GFP and Isl1 mRNA into the cardiac region of Xenopus embryos. The cement gland is indicated by dashed white circles. (G, H): Whole‐mount RNA in situ analysis of Xenopus embryos for expression of the cardiac markers nkx2–5, tbx20, and mef2d (blue) after unilateral injection of GFP alone (upper images) or in conjunction with isl1 (lower images) in the forming hearts of stage 20 Xenopus embryos. The cement gland is indicated by dashed white circles (G). Percentage of embryos with normal expression of the tested marker genes on the injected side compared to the uninjected side is indicated in the bar graph; n = 53–85 for GFP (black bars) alone and n = 67–88 for isl1 (red bars) from three to four independent experiments (H). (I, J): Whole‐mount RNA in situ of Xenopus embryos analysis for expression of the cardiac markers tnni3, myh6, and tbx5 (blue) after unilateral injection of GFP alone (upper images) or in conjunction with isl1 (lower images) in the forming hearts of stage 28 Xenopus embryos. The cement gland is indicated by dashed white circles (I). Percentage of embryos with normal expression of the tested marker genes on the injected side compared to the uninjected side is indicated in the bar graph; n = 63‐111 for GFP (black bars) alone and n = 61–78 for isl1 (red bars) from three to four independent experiments (J). (K): RT‐PCR expression analysis of Isl1 downstream target genes after bilateral injection of GFP alone or in conjunction with isl1 on heart explants of stage 24 Xenopus embryos. Changes in gene expression were observed in at least three out of four independent experiments. (L): Beating frequency of Xenopus hearts after bilateral injection of GFP mRNA alone (black filled circles) and GFP/isl1 mRNAs (black filled squares) at stage 42. Mean values ± SEM, n = 60 for GFP alone and n = 80 for GFP/isl1 from three independent experiments. Abbreviations: EB, embryoid body; GFP, green fluorescent protein; mRNA, messenger RNA.
	Figure 6. Overexpression of Isl1 promotes expression of nodal lineage markers and represses ventricular program of differentiating myocytes. (A): Expression level of genes specific for nodal and working‐myocardium lineages was determined by qRT‐PCR in GFP and Isl1OE cardiomyocytes at days 14 and 21 in independent EB differentiation experiments (as indicated by numbers). All values are normalized to Gapdh and are relative to the average expression value measured in GFP cells from differentiations 1 and 2 at day 14. p values were calculated using the Mann‐Whitney test. Minimum (min) and maximum (max) values were taken as a reference for heatmap representation. (B, C): Immunofluorescence analysis of Mlc2a (green), Mlc2v (magenta), and F‐actin (red, visualized with Phalloidin) in 1‐month‐old GFP and Isl1OE cardiomyocytes. Scale bars = 25 µm (B). Quantification of Mlc2a+, Mlc2v+ and Mlc2a/Mlc2v‐double positive myocytes from GFP (top) and Isl1OE ESCs (bottom). Mean values ± SEM, n = 189 for GFP and n = 535 for Isl1OE from five to six independent experiments (C). (D, E): Immunofluorescence analysis of Mlc2a (green), Hcn4 (magenta), and F‐actin (red, visualized with Phalloidin) in 1‐month‐old GFP and Isl1OE cardiomyocytes. Scale bars = 25 µm (D). Quantification of Hcn4+ cells in the Mlc2a+ myocyte fraction from GPF and Isl1OE ESCs. Mean values ± SEM, n = 86 for GFP and n = 83 for Isl1OE from two to three independent experiments. Abbreviation: GFP, green fluorescent protein.
	Figure 7. Isl1 overexpression affects subtype diversification of electrophysiologically functional cardiomyocytes. (A): Representative action potential (AP) traces and corresponding APD90/APD50 ratios (R) of 1‐month‐old ventricular‐, atrial‐, nodal‐like, and intermediate cardiomyocytes from GFP and Isl1OE ESCs, as determined with optical imaging using di8‐ANEPPS. (B): Quantification of 1‐month‐old ventricular‐, atrial‐, nodal‐like, and intermediate cardiomyocytes from GFP and Isl1OE ESCs based on the unique AP traits and the pharmacological response to ivabradine. Mean values ± SEM, n = 122 for GFP and n = 65 for Isl1OE from three independent experiments. (C): Percentage of reduction of early and total DD slope as well as AP frequency in 1‐month‐old nodal cardiomyocytes from GFP (black bars) and Isl1OE (red bars) ESCs after 3 µM Iva application. (D): Working model for the regulation of cardiomyocyte subtype specification by Isl1/Nkx2–5‐mediated mechanism. Abbreviations: DD, diastolic depolarization; GFP, green fluorescent protein; Iva, ivabradine.

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