Comparative genetics of cardiac chamber formation

心室形成的比较遗传学

• 批准号: 6988540
• 负责人: DEBORAH YELON
• 金额: $ 16.72万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-05 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6988540
• 关键词: animal genetic material tag; antisense nucleic acid; cardiogenesis; clinical research; developmental genetics; endoderm; gene expression; gene expression profiling; in situ hybridization; laboratory mouse; myocardium; oligonucleotides; transcription factor; vertebrate embryology; zebrafish

DESCRIPTION (provided by applicant): The identification of genetic pathways controlling cardiac chamber formation is likely to illuminate the molecular mechanisms responsible for many cardiac structural birth defects. The cardiac homeodomain transcription factor gene Nkx2-5 is known to play a key role in cardiac development: Nkx2-5 is essential for normal chamber formation in mice, and mutations in human Nkx2-5 underlie familial cases of congenital heart disease. Despite the clear importance of Nkx2-5 in the cardiac regulatory hierarchy, the downstream components of the Nkx2-5 pathway and their contributions to cardiac chamber formation are not well understood. The PIs hypothesize that the essential effector genes for cardiac chamber formation are evolutionarily conserved components of the Nkx2-5 pathway. To test this hypothesis, they propose a two-year exploratory project that combines the expertise of the Yelon and Harvey laboratories for a comparative genetic analysis of Nkx2-5 function in zebrafish and mouse. Specifically, they will begin by characterizing the molecular anatomy of the zebrafish heart as a foundation for comparative analysis. Applying this knowledge, they will compare the loss-of-function phenotypes for the Nkx2-5 gene family in zebrafish and mouse. Then, taking advantage of advances in both mouse and zebrafish genomics, they will combine microarray analysis and comparative gene expression studies to identify genes downstream of Nkx2-5 in both species. Finally, with attention focused on conserved pathway components, they will utilize zebrafish reverse genetics to test their roles during cardiac chamber formation. Together, the proposed experiments will reveal conserved roles and components of the Nkx2-5 pathway. Furthermore, by capitalizing on the complementary advantages of two model organisms, the PIs will develop a new approach for functional annotation of cardiac gene expression profiles.

描述（由申请人提供）：控制心室形成的遗传途径的识别可能阐明导致许多心脏结构出生缺陷的分子机制。已知心脏同源域转录因子基因 Nkx2-5 在心脏发育中发挥关键作用： Nkx2-5 对于小鼠正常的心室形成至关重要，而人类 Nkx2-5 的突变是先天性心脏病家族病例的基础。尽管 Nkx2-5 在心脏调节体系中具有明显的重要性，但 Nkx2-5 通路的下游成分及其对心室形成的贡献尚不清楚。 PI 假设心室形成的重要效应基因是 Nkx2-5 通路的进化保守成分。为了检验这一假设，他们提出了一个为期两年的探索性项目，该项目结合了 Yelon 和 Harvey 实验室的专业知识，对斑马鱼和小鼠的 Nkx2-5 功能进行比较遗传分析。具体来说，他们将首先描述斑马鱼心脏的分子解剖学特征，作为比较分析的基础。应用这些知识，他们将比较斑马鱼和小鼠 Nkx2-5 基因家族的功能丧失表型。然后，利用小鼠和斑马鱼基因组学的进步，他们将结合微阵列分析和比较基因表达研究来鉴定这两个物种中 Nkx2-5 下游的基因。最后，他们将注意力集中在保守的通路成分上，利用斑马鱼反向遗传学来测试它们在心室形成过程中的作用。总之，拟议的实验将揭示 Nkx2-5 通路的保守作用和组成部分。此外，通过利用两种模式生物的互补优势，PI 将开发一种心脏基因表达谱功能注释的新方法。

项目成果

An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation.

Nkx2-5/Bmp2/Smad1 负反馈环控制心脏祖细胞的规格和增殖。

• 发表时间: 2007-03-09
• 影响因子: 64.5
• 作者: Prall, Owen W J;Menon, Mary K;Solloway, Mark J;Watanabe, Yusuke;Zaffran, Stéphane;Bajolle, Fanny;Biben, Christine;McBride, Jim J;Robertson, Bronwyn R;Chaulet, Hervé;Stennard, Fiona A;Wise, Natalie;Schaft, Daniel;Wolstein, Orit;Furtado, Milen
• 通讯作者: Furtado, Milen