To the best of our knowledge, the presence of the Golgi in a belt-like ring around the nucleus has so far not been integrated in the analysis of nuclear envelope MTOCs. concluded that AKAP9 mediates microtubule nucleation at the nuclear envelope of skeletal muscle cells ( Gimpel et al., 2017).Īlong with centrosomal proteins and MTOC activity, the Golgi is localized to the nuclear envelope into a belt-like ring structure in differentiated skeletal myocytes, cardiomyocytes, and osteoclasts ( Kronebusch and Singer, 1987 Mulari et al., 2003 Tassin et al., 1985b). Based on siRNA-mediated knockdown experiments, Gimpel et al. Nesprin-1α, a member of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, is required for centrosomal protein localization and microtubule nucleation at the nuclear envelope, which contributes to proper myonuclear positioning ( Espigat-Georger et al., 2016 Gimpel et al., 2017). AKAP9 (AKAP450), PCM1, Pcnt, Cdk5rap2, Cep170, γ-tubulin, and ninein are centrosomal proteins reported to localize to the nuclear envelope during myocyte differentiation ( Bugnard et al., 2005 Fant et al., 2009 Gimpel et al., 2017 Srsen et al., 2009). The best studied cell type exhibiting a nuclear envelope MTOC is the skeletal muscle cell. The nuclear envelope of mammalian osteoclasts has also been reported to recruit Pcnt and nucleate microtubules ( Mulari et al., 2003). Concomitant with centrosomal protein relocalization, the main MTOC activity is found at the nuclear envelope ( Kronebusch and Singer, 1987 Zebrowski et al., 2015). Cell cycle exit is accompanied by a fundamental reorganization of the microtubule cytoskeleton characterized by centrosome disassembly, centriole splitting, and gradual localization of the centrosomal proteins PCM1, pericentrin (Pcnt), and Cdk5Rap2 to the nuclear envelope ( Zebrowski et al., 2015). This is associated with cell cycle exit and their terminal differentiation ( Zimmermann, 2013), where cardiomyocytes switch from hyperplastic to hypertrophic growth ( Li et al., 1996). Although non-centrosomal microtubule organization is a hallmark of many differentiated cell types, the mechanisms regulating the switch from centrosomal MTOC to ncMTOC as well as the molecular composition and regulation of ncMTOCs are just beginning to be elucidated.ĭuring late embryonic and early postnatal mammalian development, cardiac output increases, resulting in a substantial increase in mechanical load experienced by cardiomyocytes. Non-centrosomal MTOCs (ncMTOCs) are, for example, found in axons and dendrites of neurons ( Baas et al., 1988 Sánchez-Huertas et al., 2016), around the nuclear envelope of striated muscle cells ( Becker et al., 2020 Tassin et al., 1985a) and osteoclasts ( Mulari et al., 2003), as well as at the apical surface and the Golgi of epithelial cells ( Bacallao et al., 1989 Chabin-Brion et al., 2001). However, upon differentiation, many cell types organize their microtubules at non-centrosomal sites. The centrosome represents the dominant microtubule- organizing center (MTOC) in proliferating animal cells ( Bornens, 2012). Microtubule organization plays a crucial role in cell differentiation by regulating diverse cellular processes such as cell polarization, migration, mechanotransduction, organelle positioning, and intracellular transport ( Tillery et al., 2018). Collectively, we decipher the MTOC at the nuclear envelope as a bi-layered structure generating two pools of microtubules with AKAP6 as a key organizer. Finally, AKAP6 is required for cardiomyocyte hypertrophy and osteoclast bone resorption activity. Moreover, ectopic expression of AKAP6 in epithelial cells is sufficient to recruit endogenous centrosomal proteins. AKAP6 is also required for formation and activity of the nuclear envelope MTOC in human osteoclasts. Both Golgi and nuclear envelope exhibit MTOC activity utilizing either AKAP9, or Pcnt-AKAP9, respectively. In addition, AKAP6 and AKAP9 form a protein platform tethering the Golgi to the nucleus. In rat cardiomyocytes, AKAP6 anchors centrosomal proteins to the nuclear envelope through its spectrin repeats, acting as an adaptor between nesprin-1α and Pcnt or AKAP9. Here, we identify AKAP6 as key component of the nuclear envelope MTOC. The switch from centrosomal microtubule-organizing centers (MTOCs) to non-centrosomal MTOCs during differentiation is poorly understood.
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