Foxc1是进化上高度保守的转录因子，具转录激活或抑制的双向调控作用。Foxc1参与调控小鼠心脏发生，FOXC1突变与人先天性心脏病发生相关。但有关Foxc1是以何种机制调控心脏发生尚未有系统研究。我们前期工作基础表明，在斑马鱼中敲除FOXC1的直系同源基因foxc1a致心脏发生异常；基于转录组学数据的研究显示突变胚胎体节期的前部侧板中胚层和原肠期的三个胚层都正常形成，但心脏前体细胞特化标识基因nkx2.5、3个Wnt信号通路基因和3个视黄酸信号通路基因、7个pri-miRNA分别表达异常。本申请将在已有工作基础上，采用基因敲除、条件性敲除和敲入等遗传学手段，研究Foxc1a是否通过直接激活或抑制nkx2.5、3个Wnt和3个视黄酸信号通路基因、7个pri-miRNA等的表达，决定模式动物斑马鱼心脏发生。研究结果将有助于深入揭示脊椎动物心脏发生的分子机制，为了解先天性心脏病的病因提供参考。

Foxc1 is a highly conserved transcription factor during evolution. It plays dual roles by acting as a transcriptional activator or transcriptional repressor. Foxc1 is involved in regulating mouse cardiogenesis. The mutated FOXC1 is associated with the congenital heart diseases in human. However, its functions and the molecular mechanisms underlying the vertebrate cardiogenesis remain largely unknown. Previously, we demonstrated that zebrafish embryos carrying alleles of foxc1a, an orthologue gene of human FOXC1, exhibited severe defects in cardiogenesis. And our preliminary data from transcriptomic analysis further revealed that the expressions of nkx2.5 (a marker gene for the cardiac progenitor cells), 3 genes in Wnt pathway and 3 genes in retinoic acid (RA) signaling pathway，and 7 pri-miRNA, were greatly changed in zebrafish embryos though the formation of the anterior lateral plate mesoderm at somitogenesis stage and three germ layers at gastrula were normally formed. In this study, we will investigate whether foxc1a play essential roles in zebrafish cardiogenesis through directly activating or repressing the expressions of nkx2.5, the 3 genes in Wnt and the 3 ones in RA signaling pathways, and the 7 pri-miRNA in embryos by using genetic methods of creating knockout, conditional knockout and knock-in zebrafish mutants. The results from zebrafish, an excellent model for the research on vertebrate heart development, will help to reveal the molecular and genetic mechanisms of vertebrate cardiogenesis and provide clues to understand the etiology of the congenital heart diseases in human.