FGF signaling enforces cardiac chamber identity in the developing ventricle

Abstract

Atrial and ventricular cardiac chambers behave as distinct subunits with unique morphological, electrophysiological and contractile properties. Despite the importance of chamber-specific features, chamber fate assignments remain relatively plastic, even after differentiation is underway. In zebrafish, Nkx transcription factors are essential for the maintenance of ventricular characteristics, but the signaling pathways that operate upstream of Nkx factors in this context are not well understood. Here, we show that FGF signaling plays an essential part in enforcing ventricular identity. Loss of FGF signaling results in a gradual accumulation of atrial cells, a corresponding loss of ventricular cells, and the appearance of ectopic atrial gene expression within the ventricle. These phenotypes reflect important roles for FGF signaling in promoting ventricular traits, both in early-differentiating cells that form the initial ventricle and in late-differentiating cells that append to its arterial pole. Moreover, we find that FGF signaling functions upstream of Nkx genes to inhibit ectopic atrial gene expression. Together, our data suggest a model in which sustained FGF signaling acts to suppress cardiomyocyte plasticity and to preserve the integrity of the ventricular chamber.

Cre/lox‐controlled spatiotemporal perturbation of FGF signaling in zebrafish

“…Nonetheless, fgfr1‐dn‐cargo is functional in the LPM descendants, as expression of the FGF target genes etv4 and spry4 (Figs. ) was reduced at 36 hpf in pectoral fin buds when fgfr1‐dn‐cargo was triggered at 10–11 ss (14–15 hpf); and we observed cardiac phenotypes as reported for SU5402 treatment or genetic perturbations (Marques et al, ; de Pater et al, ; Pradhan et al, ; Reifers et al, ) (Fig. C).…”

Cre/lox-controlled spatio-temporal perturbation of FGF signaling in zebrafish

“…After priming in the developing LPM, triggering fgfr1-dncargo expression at 20 ss (19 hpf) resulted in disrupted pectoral fins ( Figure 6D-F), while fgfr1-dn-cargo triggered at earlier time points caused no overt pectoral fin defects. Nonetheless, fgfr1-dn-cargo is functional in the LPM descendants, as i) expression of the FGF target genes etv4 and spry4 (Figure 5, Supplementary Figure 2), and less notably dusp6 (Supplementary Figure 3), was reduced at 36 hpf in pectoral fin buds when fgfr1-dn-cargo was triggered at 10-11 ss (14-15 hpf), and ii) we observed cardiac phenotypes as reported for SU5402 treatment or genetic perturbations (de Pater et al, 2009;Marques et al, 2008;Pradhan et al, 2017;Reifers et al, 2000) ( Figure 6C). Together, these observations support an LPM-autonomous requirement for FGF activity during the critical phase of pectoral fin bud outgrowth between 18-28 hpf in zebrafish, when FGF10 and FGF24 are active in the tissue (Fischer et al, 2003;Norton et al, 2005).…”

Enrichment differentiation of human induced pluripotent stem cells into sinoatrial node-like cells by combined modulation of BMP, FGF and RA signaling pathways

“…However, increasing the dosage of BMP4 weakened the induced expression of SAN-specific markers. [26]. Further studies showed that NKX2-5 is the downstream regulator of the FGF signaling [13,14].…”