Non-canonical WNT signal transduction and cardiogenesis

非经典 WNT 信号转导和心脏发生

• 批准号: 6921185
• 负责人: LEONARD M EISENBERG
• 金额: $ 32.02万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921185
• 关键词: JUN kinase; Xenopus; Xenopus oocyte; biological signal transduction; bone morphogenetic proteins; cardiogenesis; cell differentiation; developmental genetics; enzyme activity; fibroblast growth factor; gene expression; immunocytochemistry; in situ hybridization; inhibitor /antagonist; mesoderm; nonmammalian vertebrate embryology; protein purification; protein structure function; protein tyrosine kinase

DESCRIPTION (provided by applicant): The primary step in cardiac morphogenesis is the organization of nondifferentiated mesoderm cells into bilaterally distributed precardiac fields, These heart-forming fields continue to develop as they fuse at the embryonic midline to form the primary heart tube-a process that accompanies further cell differentiation to a terminal cardiac phenotype. Several extracellular signaling factors have been implicated for promoting the formation of cardiac tissue in the early embryo. Prominent among these "cardiac promoting" factors are molecules that regulate WNT signal transduction. Data from our laboratory has demonstrated that WNT11 is an essential regulator of early cardiogenesis. However, it has also been shown that Dkk1 and crescent - molecules initially characterized as WNT inhibitors - appear to possess identical cardiac functional activities as WNT11. It is now clear that the reason these molecules share functional similarities is due to the multiplicity of WNT signaling pathways. Our research efforts have helped establish that non-canonical WNT signaling plays a major role in promoting cardiac tissue formation. Moreover, recent data has demonstrated that the similar cardiac inducing activities of WNT11, Dkk1, and crescent are due to their shared ability to activate Jun-N-terminal kinase (JNK). To build on these findings, we plan to examine in detail the functional role of these signals for formation of the heart. Accordingly, four complementary specific aims are proposed that involve examining: 1) whether WNT11/Dkk1/crescent signals promote cardiogenesis by direct action on non-differentiated mesoderm, 2) functional differences among WNT11, Dkk1, and crescent in promoting cardiac differentiation, 3) the relationship between WNT/JNK and WNT/R-catenin pathways in establishing the vertebrate heart, and 4) the involvement of noncanonical WNT signals in promoting cardiac organogenesis in conjunction with FGF and BMP proteins. These proposed studies should increase our understanding of the molecular processes that promote the formation of the heart, and may lead to insights into congenital defects.

描述（由申请人提供）：心脏形态发生的主要步骤是将非分化的中胚层细胞的组织组织为双侧分布的par体场，这些心脏形成的领域继续发展，因为它们在胚胎中线融合，以形成主要心脏管的过程，以进一步与末端心脏概念型分化。几种细胞外信号传导因子已涉及促进早期胚胎中心脏组织的形成。这些“心脏促进”因子中突出的是调节Wnt信号转导的分子。来自我们实验室的数据表明，WNT11是早期心脏病的重要调节剂。然而，也已经表明，最初以Wnt抑制剂为特征的DKK1和新月 - 分子似乎具有与WNT11相同的心脏功能活性。现在很明显，这些分子具有功能相似性的原因是由于Wnt信号通路的多样性。我们的研究工作有助于确定非典型的Wnt信号传导在促进心脏组织形成中起着重要作用。此外，最近的数据表明，WNT11，DKK1和新月的类似心脏诱导活性是由于它们共同激活Jun-N末端激酶（JNK）的能力。为了建立这些发现，我们计划详细研究这些信号在形成心脏的功能作用。因此，提出了四个涉及检查的互补特定目的：1）WNT11/DKK1/新月信号是否通过直接对非差异性中胚层进行直接作用来促进心脏病，2）Wnt11，dkk1之间的功能差异，以及在促进Wnt/Jnk和Wnt/jnk之间的关系中的wnt11，dkk1和新月之间的功能差异，3） 4）非规范WNT信号与FGF和BMP蛋白一起促进心脏器官发生。这些提出的研究应增加我们对促进心脏形成的分子过程的理解，并可能导致对先天性缺陷的见解。