Genetic analysis of the sushi domain protein Ccdc80 ub zebrafish heart development

心脏生物学中的一个基本问题是这个器官如何发育并呈现其成熟的成人形式。心脏必须在发育中的胚胎中继续维持血流，同时仍然生长并经历协调的细胞运动，将线性心管转化为复杂的结构。由于其光学清晰度，快速的外部发育和对遗传方法的顺从性，斑马鱼已成为研究基因如何调节心脏发育的有力工具。在对心脏发育中起重要作用的基因的大规模筛选中，我发现了一种突变，它影响了内膜（心脏的内层）和心肌（心脏的肌肉层）如何沟通，以确保心脏具有正确的形状和功能。 这种突变阻止了一种名为Ccdc80的蛋白质的产生。Ccdc80是一种新的、潜在的分泌型蛋白质，其功能未知，这一点引起了人们极大的兴趣。本研究计划中概述的实验旨在发现Ccdc80如何调节心脏发育。具体来说，我们将确定Ccdc80耗尽的心脏会出现什么问题。将对心脏细胞形状和基因表达模式进行详细研究。接下来，我们将确定发育中的心脏需要Ccdc80的位置，以及它的信号是如何介导的。最后，我们将通过定义在心脏发育过程中Ccdc80信号调节哪些基因来发现Ccdc80信号是如何起作用的。因此，我们将能够检查心脏发育的各个方面，这些方面只能在其他模型系统（如小鼠）中以静态方式可视化。这项工作不仅将为Ccdc80的功能提供信息，还将为促进胚胎心脏正常发育的机制提供深入了解。

A fundamental question in heart biology is how this organ develops and assumes its mature, adult form. The heart must continue to maintain blood flow in the developing embryo while still growing and undergoing concerted cell movements that convert a linear heart tube into a complex structure. Due to its optical clarity, rapid external development, and amenability to genetic approaches, the zebrafish has become a powerful tool to study how genes regulate heart development. In a large-scale screen for genes that play important roles in heart development I have identified a mutation that affects how the endocardium (inner lining of the heart) and myocardium (muscular layer of the heart) communicate to ensure that the heart assumes proper shape and function.  This mutation blocks production of a protein called Ccdc80. Of great interest is the fact that Ccdc80 is a novel, potentially secreted, protein of unknown function.The experiments outlined in this proposal aim to discover how Ccdc80 functions to regulate heart development. Specifically, we will determine what goes wrong in hearts depleted of Ccdc80. Detailed studies of heart cell shape and gene expression patterns will be undertaken. Next, we will establish where Ccdc80 is required in the developing heart, and how its signal is mediated. Finally, we will discover how the Ccdc80 signal acts by defining which genes it regulates during heart development.Heart development can be visualized in real-time in the zebrafish embryo. We will therefore be able to examine aspects of heart development that can only be visualized in a static fashion in other model systems such as the mouse. This work will not only inform as to how Ccdc80 functions, but also provide insight into the mechanisms that promote the proper development of the embryonic heart.