BMP4 triggers regulatory circuits specifying the cardiac mesoderm lineage

Cardiac lineage specification in the mouse is controlled by TGFO and WNT signaling. From fly to fish, BMP has been identified as an indispensable heart inducer. A detailed analysis of the role of Bmp4 and its effectors Smad1/5, however, was still missing. We show that Bmp4 induces cardiac mesoderm formation in murine embryonic stem cells in vitro. Bmp4 first activates Wnt3 and upregulates Nodal. pSmad1/5 and the WNT effector Tcf3 form a complex, and together with pSmad2/3 activate mesoderm enhancers and Eomes. They then cooperate with Eomes to consolidate the expression of many mesoderm factors, including T. Eomes and T form a positivefeedback loop and open additional enhancers regulating early mesoderm genes, including the transcription factor Mesp1, establishing the cardiac mesoderm lineage. In parallel, the neural fate is suppressed. Our data confirm the pivotal role of Bmp4 in cardiac mesoderm formation in the mouse. We describe in detail the consecutive and cooperative actions of three signaling pathways, BMP, WNT and Nodal, and their effector transcription factors, during

Automated summary

Cardiac lineage specification in the mouse is controlled by TGFO and WNT signaling. BMP is crucial for heart induction and Bmp4 plays a vital role in cardiac mesoderm formation. Bmp4 activates Wnt3, upregulates Nodal, and works with pSmad1/5, Tcf3, and pSmad2/3 to activate mesoderm enhancers and Eomes. The cooperation between Eomes and T form a positive feedback loop and regulate early mesoderm genes, establishing the cardiac mesoderm lineage.