Establishment and function of non-centrosomal MTOCs in striated muscle

微管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以细胞依赖的方式在不同的细胞定位产生。为什么细胞利用不同的微管组织中心（MTOCs）仍然知之甚少。最近，我们阐明了哺乳动物如何通过转录控制核膜（NE）上MTOC的形成，并破译了NE-MTOC是一个双层结构，产生两个MTs池，其中AKAP6是关键组织者。在这里，我们通过阐明NE-MTOC和NE-MTOC产生的MTs的功能，解决了横纹肌细胞为什么会形成NE-MTOC的长期问题。我们假设肌肉特异性的nesprin1 α、DMPK和CCDC141在NE-MTOC的形成中起重要作用，NE-MTOC是横纹肌细胞分化和功能所需的。为了解决这些假设，我们将阐明NE-MTOC的组装，重点是独特的nesprin1 α n端，确定DMPK和CCDC141在NE-MTOC形成中的作用，阐明NE-MTOC产生的MTs的作用，并研究条件AKAP6敲除小鼠的肌肉分化和功能。值得注意的是，近年来，已经证明了横纹肌中MTs的调节作为一种治疗方法具有很大的潜力。此外，已经确定编码核骨架和细胞骨架（LINC）复合体连接蛋白的基因突变，包括nesprin1，会导致骨骼或心脏肌病。因此，阐明NE-MTOC生成的MTs是否与LINC复合体相关，了解独特的nesprin1 α n-末端的功能，鉴定NE-MTOC形成的新调节因子，确定NE-MTOC或NE-MTOC-MTs的功能，不仅对非中心体mtoc领域和横切肌生物学家有很大的兴趣，而且对考虑横切肌疾病的社会经济负担的公众也有很大的兴趣。

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.