Role of the novel protein family CAMSAP in heart, muscle and tracheal development

描述（由申请人提供）：确定控制心脏发育的机制是促进我们对人类先天性心脏病理解的必要步骤。由于调节心脏发育的分子机制在昆虫和哺乳动物之间保守得很好，果蝇中强大的遗传工具可以用来识别新的心脏发生调节因子。我们最近对果蝇胚胎心脏发育的调控因子进行了基因筛选，发现了120多个基因，其功能是正常心脏发生所必需的。其中一种调节因子，一种名为dCAMSAP的新基因，在胚胎中胚层的离散区域表达，包括心脏和肌肉前体细胞以及胚胎气管系统。携带dCAMSAP功能缺失突变的胚胎不能完成心脏关闭，当中胚层沿着胚胎的前后轴延伸时，导致心脏撕裂。由于线性心管的形成在果蝇和脊椎动物中是一个常见的发育事件，CAMSAP蛋白的作用可能是高度保守的。除了心脏闭合缺陷外，dCAMSAP突变体还表现出类似脊椎动物骨骼肌的肌肉发育缺陷，包括成肌细胞融合缺陷和肌管引导缺陷。最后，昆虫呼吸系统（气管系统）的形态，其发育与脊椎动物血管生成相似，也在dCAMSAP突变胚胎中受到影响。dCAMSAP是一个保守但完全新颖的蛋白家族的成员，在人类和小鼠中都有代表性的成员。该项目的总体目标是确定dCAMSAP调节心脏、骨骼（躯体）肌肉和气管系统发育的分子机制，并评估这些机制在哺乳动物中的保守程度。这些研究将为心血管和骨骼肌发育和疾病的调节机制提供基本的见解。

DESCRIPTION (provided by applicant): Identifying the mechanisms that govern heart development is a necessary step to advance our understanding of congenital heart diseases in humans. Since the molecular mechanisms regulating heart development are well conserved between insects and mammals, the powerful genetic tools in Drosophila can be used to identify novel regulators of cardiogenesis. We recently performed a genetic screen for regulators of embryonic heart development in Drosophila and identified over 120 genes whose function is required for proper cardiogenesis. One of these regulators, a novel gene named dCAMSAP, is expressed in discrete domains of the embryonic mesoderm including the heart and muscle precursor cells as well as in the embryonic tracheal system. Embryos bearing a loss-of-function mutation in dCAMSAP do not complete heart closure which causes the heart to tear as the mesoderm extends along the anterior-posterior axis of the embryo. Since the formation of a linear heart tube is a common developmental event in flies and vertebrates, the role of CAMSAP proteins may be highly conserved. In addition to heart closure defects, dCAMSAP mutants show developmental defects in muscles analogous to vertebrate skeletal muscle including both myoblast fusion defects and myotube guidance defects. Finally, the morphology of the insect respiratory system (the tracheal system), whose development is similar to vertebrate angiogenesis, is also affected in dCAMSAP mutant embryos. dCAMSAP is a member of a well conserved yet completely novel protein family with representative members in both humans and mice. The overall goal of this project is to define the molecular mechanisms whereby dCAMSAP regulates heart, skeletal (somatic) muscle, and tracheal system development and to assess the extent to which these mechanisms have been conserved in mammals. These studies will provide fundamental insights into the mechanisms regulating cardiovascular and skeletal muscle development and disease.