Establishment and function of non-centrosomal MTOCs in striated muscle

横纹肌非中心体MTOC的建立和功能

• 批准号: 396080314
• 负责人: Professor Dr. Felix B. Engel
• 金额: --
• 依托单位: Professur für Experimentelle Nieren- und Herzkreislaufforschung (TRC)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/396080314?language=en
• 关键词: Establishment; function; non; centrosomal; MTOCs

Microtubule (MT) organization plays a crucial role in cell differentiation by regulating diverse cellular processes. In addition, MTs are generated at different cellular localizations in a cell-dependent manner. Why cells utilize different microtubule organizing centers (MTOCs) remains poorly understood. Recently, we have illuminated how mammals transcriptionally control MTOC formation at the nuclear envelope (NE) and deciphered the NE-MTOC as a bi-layered structure generating two pools of MTs with AKAP6 as a key organizer. Here, we address the long-lasting question why striated muscle cells establish an NE-MTOC by elucidating the function of the NE-MTOC and NE-MTOC-generated MTs. We hypothesize that the muscle-specific nesprin-1α, DMPK, and CCDC141 play important roles in NE-MTOC formation and that an NE-MTOC is required for differentiation and function of striated muscle cells. To address these hypotheses, we will elucidate the assembly of the NE-MTOC focusing on the unique nesprin-1α N-terminus, determine the role of DMPK and CCDC141 in NE-MTOC formation, elucidate the role of NE-MTOC generated MTs, and study muscle differentiation and function in conditional AKAP6 knockout mice. Notably, in recent years, it has been demonstrated that modulation of MTs in striated muscle has great potential as a therapeutic approach. In addition, it is well established that mutations in genes encoding the linker of nucleoskeleton and cytoskeleton (LINC) complex proteins, including nesprin-1, cause skeletal or cardiac myopathies. Thus, elucidating whether NE-MTOC-generated MTs are linked to the LINC complex, understanding the function of the unique nesprin-1α N-terminus, identifying new modulators of NE-MTOC formation, and determining the function of the NE-MTOC or NE-MTOC-MTs will not only of great interest to the field of non-centrosomal MTOCs and striated muscle biologist but to the general public considering the socioeconomic burden of striated muscle disease.

微管（MT）组织通过调节多种细胞过程在细胞分化中起着至关重要的作用。此外，MT以依赖于细胞的方式在不同的细胞定位处生成。为什么细胞利用不同的微管组织中心（MTOC）仍然知之甚少。最近，我们已经阐明了哺乳动物如何转录控制MTOC形成的核膜（NE）和解密的NE-MTOC作为一个双层结构产生两个池的MT与AKAP 6作为一个关键的组织者。在这里，我们解决长期存在的问题，为什么横纹肌细胞建立一个NE-MTOC的NE-MTOC和NE-MTOC生成的MT的功能阐明。我们推测肌肉特异性nesprin-1α、DMPK和CCDC 141在NE-MTOC形成中起重要作用，并且NE-MTOC是横纹肌细胞分化和功能所必需的。为了解决这些假设，我们将阐明NE-MTOC的组装，重点是独特的nesprin-1α N-末端，确定DMPK和CCDC 141在NE-MTOC形成中的作用，阐明NE-MTOC产生的MT的作用，并研究条件性AKAP 6敲除小鼠的肌肉分化和功能。值得注意的是，近年来，已经证明横纹肌中MT的调节作为治疗方法具有很大的潜力。此外，已充分确定编码核骨架和细胞骨架（LINC）复合物蛋白（包括nesprin-1）的接头的基因中的突变引起骨骼肌或心肌病。因此，阐明NE-MTOC产生的MT是否与LINC复合物连接，了解独特的nesprin-1α N-末端的功能，鉴定NE-MTOC形成的新调节剂，并确定NE-MTOC或NE-MTOC-MT的功能，不仅对非中心体MTOC和横纹肌生物学家领域具有极大的兴趣，而且对考虑到横纹肌疾病的社会经济负担的公众也具有极大的兴趣。