Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Sequencing Core Facility, Max Planck Institute for Molecular Genetics,14195 Berlin, Germany.
Development. 2023 May 15;150(10). doi: 10.1242/dev.201450. Epub 2023 May 22.
Cardiac lineage specification in the mouse is controlled by TGFβ 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 positive- feedback 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 cardiac mesoderm specification.
心脏谱系在小鼠中的特化受 TGFβ 和 WNT 信号的控制。从果蝇到鱼类，BMP 已被确定为必不可少的心脏诱导物。然而，Bmp4 及其效应物 Smad1/5 的作用的详细分析仍缺失。我们表明 Bmp4 在体外诱导小鼠胚胎干细胞形成心脏中胚层。Bmp4 首先激活 Wnt3 并上调 Nodal。pSmad1/5 和 WNT 效应物 Tcf3 形成复合物，并与 pSmad2/3 一起激活中胚层增强子和 Eomes。然后它们与 Eomes 合作巩固许多中胚层因子的表达，包括 T。Eomes 和 T 形成正反馈回路并开启调节早期中胚层基因的其他增强子，包括转录因子 Mesp1，建立心脏中胚层谱系。同时，神经命运被抑制。我们的数据证实了 Bmp4 在小鼠心脏中胚层形成中的关键作用。我们详细描述了 BMP、WNT 和 Nodal 这三种信号通路及其效应转录因子在心脏中胚层特化过程中的连续和协同作用。
