BMP-mediated inhibition of FGF signaling promotes cardiomyocyte differentiation of anterior heart field progenitors

The transition from progenitor to differentiated cells is critical for successful organogenesis; subtle alterations in this process can lead to developmental disorders. The anterior heart field (AHF) encompasses a niche in which cardiac progenitors maintain their multipotent and undifferentiated nature by signals from the surrounding tissues, which thus far have been poorly defined. Using systems biology approaches and perturbations of signaling molecules in chick embryos, we revealed a tight crosstalk between the bone morphogenic protein (BMP) and fibroblast growth factor (FGF) signaling pathways within the AHF: BMP4 promotes myofibrillar gene expression and cardiomyocyte contractions, by blocking FGF signaling. Furthermore, inhibition of the FGF-ERK pathway is both sufficient and necessary for these processes, suggesting that FGF signaling blocks premature differentiation of cardiac progenitors in the AHF. Investigating the molecular mechanisms downstream to BMP signaling revealed that BMP4 induced a set of neural crest-related genes; including MSX1, which was sufficient to induce cardiomyocyte differentiation. We suggest that BMP and FGF signaling pathways act via inter- and intra-regulatory loops in multiple tissues, to coordinate the balance between proliferation and differentiation of cardiac progenitors.

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Tirosh-Finkel L, Zeisel A, Brodt-Ivenshitz M, Shamai A, Yao Z, Seger R, Domany E, Tzahor E