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非常保守，因此果蝇中强大的遗传工具可用于鉴定心脏发生的新调节剂。我们最近进行了果蝇胚胎心脏发育的调节基因筛选，并确定了120多个基因，其功能是正确的心脏发生所必需的。其中一种调节因子是一种名为dCAMSAP的新基因，该基因在胚胎中胚层的离散结构域中表达，包括心脏和肌肉前体细胞以及胚胎气管系统。携带dCAMSAP中功能丧失突变的胚胎不完成心脏闭合，这导致心脏在中胚层沿胚胎的前-后轴沿着延伸时撕裂。由于线状心管的形成是果蝇和脊椎动物中常见的发育事件，因此CAMSAP蛋白的作用可能是高度保守的。除了心脏闭合缺陷之外，dCAMSAP突变体在类似于脊椎动物骨骼肌的肌肉中显示发育缺陷，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，其发展是类似于脊椎动物血管生成，也受到影响，在dCAMSAP突变胚胎。dCAMSAP是一个非常保守但完全新的蛋白质家族的成员，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、骨骼肌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。这些研究将为调节心血管和骨骼肌发育和疾病的机制提供基本见解。

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.