Identification of human cardiomyogenic factor

心脏形成的关键事件是中胚层细胞在原肠胚形成过程中向胚胎的前外侧区域迁移。在这个过程中，形态发生运动和心脏命运决定是由细胞因子调节的。这些分泌蛋白在两栖动物和鸟类心脏转录因子的诱导和心肌细胞分化中发挥重要作用。心肌生成信号确实激活了心脏特异性转录因子（Csx/Nkx2.5, Gata4, Mef2c）的表达，这些转录因子激活了循环激素和心脏特异性蛋白的表达。Wnt家族蛋白也与胚胎发育和心肌形成有关。在果蝇中，“无翅”是脊椎动物Wnt的同系物，它通过“犰狳”参与“tinman”的表达，并推动心脏发育。然而，在脊椎动物中，Wnt1/3a可以激活典型的Wnt/b-catenin信号通路，通过糖原合成酶激酶3b的失活来稳定b-catenin，从而抑制心脏中胚层的心肌细胞分化。Wnt11通过非规范途径促进爪蟾和小鼠胚胎细胞系的心脏分化。Wnt抑制剂的分泌可阻止神经管分泌的Wnt3a抑制心脏形成。在这项研究中，我们进行了GeneChip分析来鉴定多种细胞外决定因素，并通过NIA阵列分析（http://lgsun.grc.nia.nih.gov/ANOVA/）评估差异基因表达的统计学意义。NIA阵列分析是一种基于网络的微阵列数据分析工具。我们发现Grem1增强了确定的心肌形成途径，并且BMP信号通路的抑制至少部分参与了Grem1促进心肌形成的初始决定。

The critical event in heart formation is commitment of mesodermal cells to a cardiomyogenic fate and their migration into anterolateral regions of the embryo during gastrulation. In this process, morphogenic movements and cardiac fate determination are regulated by cytokines. These secreted proteins play important roles in induction of cardiac transcription factors and differentiation of cardiomyocytes in amphibians and avians. Cardiomyogenic signals, indeed activate expression of cardiac specific transcriptional factors (Csx/Nkx2.5, Gata4, Mef2c), and these transcriptional factors activate expression of circulating hormones and cardiac specific proteins. Wnt family proteins have also been implicated in embryonic development, and cardiomyogenesis. In Drosophila, 'wingless', a homologue of vertebrate Wnt is involved in expression of 'tinman', through 'armadillo', and drives heart development. In vertebrates, however, Wnt1/3a, which activates the canonical Wnt/b-catenin signaling pathway leading to stabilization of b-catenin through inactivation of glycogen synthase kinase-3b, inhibits cardiomyocytic differentiation from cardiac mesoderm. Wnt11 promotes cardiac differentiation via the non-canonical pathway in Xenopus and murine embryonic cell lines. The secretion of Wnt inhibitors prevents Wnt3a secreted by the neural tube from inhibiting heart formation. In this study, we performed GeneChip analysis to identify multiple extracellular determinants, and evaluated the statistical significance of differential gene expression by NIA array analysis (http://lgsun.grc.nia.nih.gov/ANOVA/), a web-based tool for microarray data analysis. We found that Grem1 enhances the determined path to cardiomyogenesis, and that inhibition of the BMP signaling pathway is, at least in part, involved in initial determination of Grem1-promoted cardiomyogenesis.