An important role of Osr1 in outflow tract development

Osr1 在流出道发育中的重要作用

• 批准号: 9565801
• 负责人: LingLin Xie
• 金额: $ 36.67万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9565801
• 关键词: Address; Aorta; Atrial Heart Septal Defects; Candidate Disease Gene; Cell Cycle; Cell Lineage; Cell Proliferation; Cells; ChIP-seq; Congenital Heart Defects; Data; Defect; Development; Dorsal; Double Outlet Right Ventricle; Embryo; Encyclopedias; Equilibrium; Etiology; Genes; Genetic; Genome; Genomic Segment; Growth; Heart; Heart Abnormalities; Knockout Mice; Knowledge; Live Birth; Lung; Mesoderm; Mission; Modeling; Molecular; Molecular Genetics; Mutant Strains Mice; Mutation; Ontology; Pathway Analysis; Pattern; Penetration; Play; Prevention; Proteins; Public Health; Regulation; Regulator Genes; Reporting; Research; Role; Rotation; Signal Transduction; Testing; Transcriptional Regulation; United States National Institutes of Health; Venous; Work; Zinc Fingers; base; cardiogenesis; cdc Genes; dosage; insight; novel; precursor cell; smoothened signaling pathway; transcription factor; transcriptome sequencing

Project Summary Congenital heart defect (CHD) occurs in nearly 1 of 1000 live births, and approximately one third involves malformations of the cardiac outflow tract (OFT). Double outlet right ventricle (DORV) and overriding aorta (AO) are anomalies resulting from OFT misalignment. Currently the etiology of CHDs associated with OFT misalignment is largely unknown and the cellular, genetic, molecular basis of OFT development has remained elusive. Osr1 encodes a zinc finger protein and is strongly expressed in the dorsal mesocardium during early heart development. We found that precursor cells expressing Osr1 contributed to the pulmonary trunk and deletion of Osr1 caused DORV or OA. The Osr1 null mouse embryos had OFT rotation problem and had abnormal patterning of the SHF precursor cells in the dorsal mesocardium, which might result from proliferation defects in SHF. Interestingly, we and others reported that reduction of Pten, a well-established negative proliferation regulator, could rescue SHF proliferation defects, implying an inhibition role of Pten in modulating Osr1 regulated-SHF proliferation. We further identified potential Osr1 direct targets: Cdk6 and CycD2 involving cell cycle regulators, and Hh-signaling modulator Smo. The latter suggested an interaction between Osr1 and Hh-signaling, which is further supported by the finding that double compound heterozygous mutation of Osr1 and Smo caused a high penetration of DORV. Overall, these results strongly suggested a genetic regulatory of Osr1, Hh-signaling and cell cycle genes in SHF for OFT development. We hypothesize: Balanced by Pten inhibition, Osr1 modulates proliferation in SHF during OFT development by transcriptional regulation of proliferation related genes and Hh-signaling. To test this hypothesis, we propose the following three aims: (1) to determine how Osr1 modulates SHF cell proliferation for proper OFT alignment; (2) to investigate if and how Osr1 functions upstream of Hh-signaling in regulating OFT development; (3) to determine that Osr1 regulation on SHF proliferation and DORV is balanced by Pten inhibition. This work will uncover new candidate genes and mechanisms underlying common forms of CHDs.

项目摘要 先天性心脏缺陷（CHD）发生在1000个活产中的近1个，大约三分之一涉及 心脏出口区的畸形（OFT）。双出口右心室（DORV）和覆盖主动脉（AO） 是经常错位引起的异常。目前，与Fast未对准有关的CHD的病因 在很大程度上是未知的，并且经常发育的细胞，遗传，分子基础仍然难以捉摸。 OSR1编码 锌指蛋白质在早期心脏发育期间在心肌中强烈表达。我们发现 表达OSR1的前体细胞有助于OSR1的肺部躯干和缺失导致DORV或OA。 OSR1无效小鼠胚胎经常出现旋转问题，并且在SHF前体细胞中具有异常模式 背上的心肌可能是由SHF中的增殖缺陷引起的。有趣的是，我们和其他人报告 PTEN的减少是一个公认的负增殖调节剂，可以挽救SHF增殖缺陷， 暗示PTEN在调节OSR1调节-SHF增殖中的抑制作用。我们进一步确定了潜力 OSR1直接靶标：CDK6和CYCD2涉及细胞周期调节剂，以及HH信号调节剂SMO。后来 建议OSR1和HH-SIGNALING之间的相互作用，这进一步支持了双重的发现 OSR1和SMO的复合杂合突变引起了DORV的高渗透。总体而言，这些结果强烈 建议在SHF中进行OSR1，HH信号和细胞周期基因的遗传调节，以进行FAST发育。我们 假设：通过PTEN抑制平衡，OSR1在OFT开发过程中调节SHF的增殖 相关基因和HH信号的转录调节。为了检验这一假设，我们提出了 以下三个目的：（1）确定OSR1如何调节SHF细胞增殖以进行适当的比对； （2）至 调查OSR1在确定OFT开发中是否在HH信号上游的功能； （3）确定 OSR1对SHF增殖和DORV的调节是通过PTEN抑制平衡的。这项工作将揭示新的候选人 CHD的共同形式的基因和机制。