Regulation of actin dynamics during myofibril assembly

肌动蛋白细胞骨架的动态重组是通过协调调节肌动蛋白细丝的组装和拆卸来完成的。在多细胞生物中，不同类型的细胞利用不同的机制来调节肌动蛋白细丝的动力学。特别是在肌肉细胞中，肌动蛋白细胞骨架分化为肌原纤维，肌原纤维是高度组织化的收缩装置。这个项目的长期目标是了解肌动蛋白细胞骨架在肌肉发育过程中重组为肌原纤维的机制。这项研究的预期结果将为深入了解细胞细胞器形态发生的分子基础提供依据。这项拟议的项目将以线虫秀丽线虫为模型系统，探索肌动蛋白解聚因子(ADF)/cofilin在肌肉发育过程中肌动蛋白细丝动力学中的作用。ADF/cofilin通过解聚和切断肌动蛋白细丝来增强肌动蛋白细丝的动力学。在线虫中，编码肌肉特有的ADF/cofilin亚型的基因突变会导致肌肉细胞中肌动蛋白细丝的混乱。这些研究表明，肌肉特异的ADF/cofilin是在肌原纤维组装过程中产生肌动蛋白细丝动态的关键因素。本项目的目的是：(A)确定肌肉特异性的ADF/cofilin在体外对肌动蛋白细丝动力学的影响；(B)确定ADF/cofilin在体内肌原纤维组装中切断和解聚的具体作用；(C)确定ADF/cofilin的调节器的作用。

Dynamic reorganization of actin cytoskeleton is accomplished by a coordinated regulation of assembly and disassembly of actin filaments. In multicellular organisms, various types of cells utilize different mechanisms to regulate actin filament dynamics. Especially in muscle cells, the actin cytoskeleton is differentiated into myofibrils, which are highly organized contractile apparatuses. The long-term objective of this project is to understand the mechanisms by which the actin cytoskeleton is reorganized into myofibrils during muscle development. The expected outcome of this research will provide insight into molecular basis of morphogenesis of cellular organelles. This proposed project will use the nematode Caenorhabditis elegans as a model system and explore the roles of actin depolymerizing factor (ADF)/cofilin in actin filament dynamics during muscle development. ADF/cofilin enhances actin filament dynamics by depolymerizing and severing actin filaments. In C. elegans, mutations in a gene encoding a muscle-specific ADF/cofilin isoform cause disorganized actin filaments in muscle cells. These studies have suggested that the muscle-specific ADF/cofilin is a critical factor to generate a dynamic state of actin filaments during myofibril assembly. The aims of this project are: (a) to determine the effects of the muscle-specific ADF/cofilin on actin filament dynamics in vitro, (b) to determine specific roles of severing and depolymerization by ADF/cofilin in myofibril assembly in vivo, (c) to determine the roles of modulators of ADF/cofilin.