Wnt/β-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells
Wnt/β-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells
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DOI：
10.1073/pnas.1121236109
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发表时间：
2012-07-03
影响因子：
11.1
通讯作者：
Birchmeier, Walter
中科院分区：
文献类型：
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作者：
Klaus, Alexandra;Mueller, Marion;Birchmeier, Walter
第一和第二心脏区祖细胞的分化依赖于心脏特异性转录因子。通过小鼠胚胎的条件诱变，我们确定了在胚胎第9天心脏祖细胞分化过程中控制心脏特异性转录因子表达的信号事件等级。在这个发育阶段，Wnt/ β -连环蛋白和Bmp作用于Notch/RBPJ的下游。典型Wnt信号负调控因子Axin2的突变可增强Wnt和Bmp4信号，足以挽救RBPJ缺失导致的心脏分化停止。利用FACS富集RBPJ和RBPJ/Axin2突变体的心脏祖细胞，在Bmp抑制剂Noggin存在的胚胎培养中，通过将Bmp4突变交叉到RBPJ/Axin2突变背景中，我们发现Wnt和Bmp4信号激活心脏祖细胞中特异性和非重叠的心脏特异性基因：Nkx2-5、Isl1和Baf60c由Wnt/ β -catenin控制，Gata4、SRF和Mef2c由Bmp信号控制。我们的研究有助于理解心脏祖细胞分化和流出道发育的调控层次，并对理解和模拟心脏发育具有重要意义。
Progenitor cells of the first and second heart fields depend on cardiac- specific transcription factors for their differentiation. Using conditional mutagenesis of mouse embryos, we define the hierarchy of signaling events that controls the expression of cardiac-specific transcription factors during differentiation of cardiac progenitors at embryonic day 9.0. Wnt/beta-catenin and Bmp act downstream of Notch/RBPJ at this developmental stage. Mutation of Axin2, the negative regulator of canonical Wnt signaling, enhances Wnt and Bmp4 signals and suffices to rescue the arrest of cardiac differentiation caused by loss of RBPJ. Using FACS enrichment of cardiac progenitors in RBPJ and RBPJ/Axin2 mutants, embryo cultures in the presence of the Bmp inhibitor Noggin, and by crossing a Bmp4 mutation into the RBPJ/Axin2 mutant background, we show that Wnt and Bmp4 signaling activate specific and nonoverlapping cardiac-specific genes in the cardiac progenitors: Nkx2-5, Isl1 and Baf60c are controlled by Wnt/beta-catenin, and Gata4, SRF, and Mef2c are controlled by Bmp signaling. Our study contributes to the understanding of the regulatory hierarchies of cardiac progenitor differentiation and outflow tract development and has implications for understanding and modeling heart development.