Role of the Embryonic Node in Cardiac Development and Congenital Heart Disease

胚胎节点在心脏发育和先天性心脏病中的作用

• 批准号: 8056809
• 负责人: Stephanie M Ware
• 金额: $ 37.5万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056809
• 关键词: Animal Model; Binding; Biological Assay; Cardiac; Cardiovascular system; Carrier Proteins; Categories; Cell Nucleus; Cells; Cilia; Complex; Congenital Abnormality; Congenital Heart Defects; Cytoplasm; Data; Defect; Dental crowns; Development; Diagnostic; Embryo; Embryonic Development; Erinaceidae; Genetic; Goals; Handedness; Human; In Vitro; Knock-in Mouse; Lateral; Left; Ligands; Limb Bud; Link; Maintenance; Mediating; Mediator of activation protein; Mesoderm; Molecular; Molecular Genetics; Morphogenesis; Morphology; Mus; Mutation; Neural tube; Nodal; Nuclear Localization Signal; Organ; Output; Pathway interactions; Patients; Pattern; Phenotype; Proteins; Randomized; Research Personnel; Role; Side; Signal Transduction; Signal Transduction Pathway; Situs Inversus; Staging; Testing; Therapeutic Intervention; Tissues; Trans-Activators; Transfection; Visceral; Zinc Fingers; base; cell type; chromatin immunoprecipitation; congenital heart disorder; design; fluid flow; gastrulation; hedgehog signal transduction; human SMO protein; in vivo; loss of function; malformation; member; molecular marker; mutant; novel; receptor; research study; response; smoothened signaling pathway; tool; transcription factor

DESCRIPTION (provided by applicant): Congenital heart defects are the most common type of birth defect, occurring in just less than 1% of all livebirths. One category of heart defects, heterotaxy, is thought to result from abnormal left-right patterning during embryogenesis. In its X-linked form, heterotaxy results from mutations in Zic3, a member of the Gli superfamily of transcription factors. Gli proteins are mediators of hedgehog signaling during development, and Zic3 is a candidate for a cell type specific trans-activator of hedgehog signaling at the node. The long term goal of this study is to define genetic and molecular interactions during L-R patterning that are required for cardiac morphogenesis. We have shown that mutations in ZIC3 result in abnormal subcellular localization in vitro, and that mice deficient in Zic3 recapitulate the phenotype identified in patients. Further, we have demonstrated that Zic3 acts upstream of a conserved signal transduction pathway acting at the embryonic node to control left-right patterning. In addition to Zic3's known expression in perinodal cells, we have recent data identifying expression in the cilia of the node. We hypothesize that the subcellular localization of Zic3 in the node and perinodal crown cells is critical for transduction of hedgehog signaling, determination of left- right patterning, and subsequent cardiac looping morphogenesis. The proposed experiments are designed to determine the tissue-, cell-type, and subcellular specific roles of Zic3 and examine the consequences of alteration of Zic3 expression on hedgehog signal transduction. Aim1 will test the cell autonomous requirement for Zic3 in perinodal crown cells for proper cardiac development and looping morphogenesis via a conditional loss of function approach. Aim 2 will test the hypothesis that alteration in the subcellular localization of Zic3 changes the net hedgehog signaling output from the node and lowers the threshold for cardiac and midline developmental defects. An understanding of the molecular hierarchy controlling cardiac looping is a necessary prerequisite for the development of genetic diagnostics and therapeutic interventions. These studies have the potential to identify molecular and genetic pathways contributing to cardiac development and will develop novel tools to dissect mechanisms underlying congenital heart disease.

描述（由申请人提供）：先天性心脏病是最常见的出生缺陷类型，仅占所有活产婴儿的不到 1%。一类心脏缺陷，即异位性，被认为是胚胎发生过程中左右模式异常造成的。在 X 连锁形式中，异源性是由转录因子 Gli 超家族成员 Zic3 的突变引起的。 Gli 蛋白是发育过程中 hedgehog 信号传导的介质，而 Zic3 是节点处 hedgehog 信号传导的细胞类型特异性反式激活剂的候选者。这项研究的长期目标是定义心脏形态发生所需的 L-R 模式形成过程中的遗传和分子相互作用。我们已经证明，ZIC3 突变会导致体外亚细胞定位异常，并且 Zic3 缺陷的小鼠重现了在患者中发现的表型。此外，我们还证明了 Zic3 作用于胚胎节点的保守信号转导通路的上游，以控制左右模式。除了 Zic3 在节周细胞中的已知表达之外，我们还有最近的数据鉴定了节点纤毛中的表达。我们假设 Zic3 在节和节周冠细胞中的亚细胞定位对于刺猬信号转导、左右模式的确定以及随后的心脏循环形态发生至关重要。所提出的实验旨在确定 Zic3 的组织、细胞类型和亚细胞特异性作用，并检查 Zic3 表达改变对刺猬信号转导的影响。 Aim1 将通过条件性功能丧失方法测试节周冠细胞对 Zic3 的细胞自主需求，以实现适当的心脏发育和循环形态发生。目标 2 将检验以下假设：Zic3 亚细胞定位的改变会改变节点的净 hedgehog 信号输出，并降低心脏和中线发育缺陷的阈值。了解控制心脏循环的分子层次是发展遗传诊断和治疗干预的必要先决条件。这些研究有可能确定有助于心脏发育的分子和遗传途径，并将开发新的工具来剖析先天性心脏病的机制。

项目成果

Use of FOXJ1CreER2T mice for inducible deletion of embryonic node gene expression.

使用 FOXJ1CreER2T 小鼠诱导胚胎节点基因表达缺失。

• DOI: 10.1002/dvg.20467
• 发表时间: 2009
• 期刊: Genesis (New York, N.Y. : 2000)
• 作者: Wang,Shuyun;Ware,StephanieM
• 通讯作者: Ware,StephanieM

The Role of the Geneticist and Genetic Counselor in an ACHD Clinic.

遗传学家和遗传咨询师在 ACHD 诊所中的作用。

• DOI: 10.1016/j.ppedcard.2012.05.004
• 发表时间: 2012
• 期刊: Progress in pediatric cardiology
• 影响因子: 0.9
• 作者: Parrott,Ashley;Ware,StephanieM
• 通讯作者: Ware,StephanieM

Heterotaxy-spectrum heart defects in Zic3 hypomorphic mice.

• DOI: 10.1038/pr.2013.147
• 发表时间: 2013-11
• 期刊: PEDIATRIC RESEARCH
• 影响因子: 3.6
• 作者: Haaning, Allison M.;Quinn, Malgorzata E.;Ware, Stephanie M.
• 通讯作者: Ware, Stephanie M.

A mouse model of conduction system patterning abnormalities in heterotaxy syndrome.

异位综合征中传导系统异常的小鼠模型。

• DOI: 10.1203/pdr.0b013e3181ee0028
• 发表时间: 2010
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Czosek,RichardJ;Haaning,Allison;Ware,StephanieM
• 通讯作者: Ware,StephanieM

Identification of a novel ZIC3 isoform and mutation screening in patients with heterotaxy and congenital heart disease.

• DOI: 10.1371/journal.pone.0023755
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bedard JE;Haaning AM;Ware SM
• 通讯作者: Ware SM