Establishment and function of non-centrosomal MTOCs in striated muscle

• Applicant: Professor Dr. Felix B. Engel
• Subject Area: Cell Biology ; Developmental Biology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 396080314

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.

• DFG Programme: Research Grants