FLNC在胚胎心脏发育中的功能及相关机制研究

在胚胎心脏发育早期，心肌细胞外机械信号通过细胞膜上的抗肌萎缩蛋白-糖蛋白复合体（DGC）传递到细胞内，调控心肌细胞增殖。肌聚糖（SAG）是DGC中识别细胞信号的重要组成部分。细丝蛋白C（FLNC）是一种细胞骨架蛋白，可特异性结合SAG和ERK1/2。我们前期研究发现：在胚胎早期敲除小鼠心肌细胞中的FLNC，小鼠表现为胚胎心肌细胞增殖能力下降、心脏发育异常，并在胚胎早期全部死亡。特异性敲除FLNC后，GSEA分析提示心肌细胞增殖相关通路发生显著变化；RNA-Seq分析提示与细胞增殖密切相关的ERK1/2表达显著下调。因此，我们推测：心脏发育过程中，FLNC可能是信号传导枢纽，将SAG识别的细胞外增殖信号向细胞内传递并通过ERK1/2途径调控胚胎心肌细胞的增殖和心脏发育。本研究拟在细胞和动物水平进一步研究FLNC在胚胎心脏发育中的功能及其分子机制，为防治先心病提供新思路。

In the early stage of heart development, extracellular mechanical signals are transmitted into the cardiomyocyte through the dystrophin-associated glycoprotein complex (DGC), which then regulates the proliferation of cardiomyocytes. Sarcoglycan(SAG) is one of the most important proteins of DGC to recognize and transmit extracellular signals. Filamin C (FLNC) is a cytoskeletal protein that can specifically binds SAG and ERK1/2. Our previous studies found that when FLNC was knocked out from mouse embryonic cardiomyocytes, the knockout mice showed reduced cardiomyocytes proliferation, abnormal cardiac development, and all knockout mice died in early embryonic stage. After FLNC was knocked out, GSEA analysis indicated that the proliferation-related pathways changed dramatically, and RNA-Seq analysis showed that the expression of ERK1/2, which is related to cell proliferation, was significantly down-regulated. Therefore, we propose that during cardiac development, FLNC may serve as a signal transduction hub, which transmits SAG-identified extracellular proliferative signals to the inside of cell and mediates proliferative genes’ expression through the ERK1/2 pathways, and eventually regulating embryonic cardiomyocytes proliferation and heart development. This study intends to further discover the role and mechanism of FLNC in embryonic cardiomyocytes proliferation and heart development, providing new ideas and interventions for congenital heart disease.