Tbx18通过下调EMT信号分子参与调控心脏发育

The Transcription Factor Tbx18 Control Major Epithelial-to-mesenchymal Transition-associated Signaling Molecules in Mouse Heart Development

转录因子Tbx18(Tbx18)在小鼠胚胎心外膜上皮细胞表达并调控心外膜上皮细胞向心系细胞分化.上皮间充质转化(EMT)过程是器官发育和形成的重要机制.为阐述Tbx18通过调控下游EMT关键信号分子参与心外膜上皮细胞分化和心脏发育,本研究运用Tbx18-Cre/Rosa26R-EYFP双杂合基因敲入小鼠和免疫荧光共聚焦,证实Tbx18+心系细胞和EMT关键信号分子Snail1、Smad、Slug、Twist在发育后期胚鼠心外膜和心外膜下间充质发生共聚焦.同时还发现,Tbx18在胚鼠不同发育阶段的表达模式和Tbx18+心系细胞内上述EMT关键信号分子的表达模式相似.Tbx18和EMT关键信号分子在发育心脏存在相似的时空表达模式,因此,它们之间可能存在相互调控作用.运用Tbx18突变技术揭示了Tbx18突变型胚鼠心脏EMT关键信号分子表达水平均较野生型显著下调,直接证实了上述4个EMT信号分子是Tbx18的可能靶点.理解Tbx18参与心脏发育的下游靶点有助于改善成年心脏损伤后的再生修复.

T-box transcription factor Tbxl8 （Tbxl8） was expressed in epicardial cells and controls the differentiation of epicardial epithelial cells into myocardial lineage in the developing mouse embryo. Epithelial-to-mesenchymal transition （EMT） plays a crucial role in embryonic development. For the purpose of determine whether Tbxl8 regulates downstream EMT-associated signaling molecules, such as the transcriptional factors Snaill, Slug, Smad, Twist and cell adhesion molecule E-cadherint in mouse heart development. In this study, we used the Tbx18-Cre/Rosa26R-EYFP double-heterozygous mice and Tbxl8 mutants to investigate the spatiotemporal expressions patterns of the major EMT-associated signaling molecules within Tbxl8 lineage cells. We observed that the major EMT-associated transcriptional factors co-localized with Tbxl8 lineage cells in the epicedium and subepicardial mesenchyme. The expression patterns of the major EMT-associated signaling molecules within Tbx 18 lineage cells were consistent with Tbx 18. Most important, we further demonstrate that the four EMT-associate transcriptional factors are reduced and E-cadherin is significantly increased in the Tbxl8 mutant hearts compared with the wild type hearts. Our data together indicated that Tbxl8 regulated the major EMT-associated major signaling molecules in mouse heart development. Understanding the signaling pathways by which Tbxl 8 regulates mouse heart development may help to improve regeneration in adult heart disease.