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Type III Intermediate Filaments Desmin, Glial Fibrillary Acidic Protein (GFAP), Vimentin, and Peripherin

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Type III Intermediate Filaments Desmin, Glial Fibrillary Acidic Protein (GFAP), Vimentin, and Peripherin Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Type III Intermediate Filaments Desmin, Glial Fibrillary Acidic Protein (GFAP), Vimentin, and Peripherin Elly M. Hol1,2,3 and Yassemi Capetanaki4 1Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands 2Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands 3Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, 1098 XH Amsterdam, The Netherlands 4Center of Basic Research, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece Correspondence: [email protected]; [email protected] SUMMARY Type III intermediate filament (IF) proteins assemble into cytoplasmic homopolymeric and heteropolymeric filaments with other type III and some type IV IFs. These highly dynamic structures form an integral component of the cytoskeleton of muscle, brain, and mesenchymal cells. Here, we review the current ideas on the role of type III IFs in health and disease. It turns out that they not only offer resilience to mechanical strains, but, most importantly, they facil- itate very efficiently the integration of cell structure and function, thus providing the necessary scaffolds for optimal cellular responses upon biochemical stresses and protecting against cell death, disease, and aging. Outline 1 Introduction 5 Vimentin 2 Desmin 6 Conclusion 3 GFAP References 4 Peripherin Editors: Thomas D. Pollard and Robert D. Goldman Additional Perspectives on The Cytoskeleton available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a021642 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a021642 1 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press E.M. Hol and Y. Capetanaki 1 INTRODUCTION (Capetanaki 2002; Capetanaki et al. 2015), appearing first at day 7.5 postcoitum in the precardial mesoderm, and a There are four proteins classified as type III intermediate day later in the skeletal muscle progenitors, the myotome filament (IF) proteins: desmin, glial fibrillary acidic protein of the somites, in which its expression precedes even the (GFAP), peripherin, and vimentin. Desmin is expressed in myogenic helix–loop–helix (HLH) transcription regula- all muscle types, GFAP is expressed in astrocytes and other tors MyoD, myogenin, and MRF4 (Buckingham et al. glial cells, and peripherin is expressed in peripheral neu- 1992). All these factors, in cooperation with members of rons. Vimentin is the most widely distributed and studied the MEF2 family of transcription regulators, control des- type III IF protein, expressed mainly in mesenchyme-de- min expression during development (Li and Capetanaki rived cells, undifferentiated cells, and most cells in culture. 1994; Kuisk et al. 1996), thus suggesting a regulatory role Type III IF proteins can form coiled-coil dimers with them- for desmin during myogenic commitment and differenti- selves, other type III IF members, and type IV IF proteins ation. Desmin is also expressed in adult skeletal and car- such as syncoilin, nestin, neurofilaments, and synemins. All diac muscle progenitor cells (Allen et al. 1991; Pfister et al. type III IF proteins are cytoplasmic IFs and have a similar 2005). primary structure, consisting of a head, rod, and tail do- main (Fig. 1). Here, we review the expression of the differ- ent type III IFs during development and in adulthood, 2.1.2 Nuclear Role as a Myogenic and Cardiogenic before moving on to focus on their role in health and Cytoskeletal Regulator disease. During myogenesis and cardiogenesis, extensive mechano- chemical signal transduction from the cell surface to the 2 DESMIN nucleus takes place, and the IF cytoskeletal and nucleoske- 2.1 Desmin in Muscle Development letal systems are potential modulators of such actions be- cause they form a continuous network that links directly or 2.1.1 Expression Pattern in Cardiac and Skeletal through the LINC (“linker of the nucleoskeleton and the Muscle Progenitors cytoskeleton”) complex, the outside of the cell to the nu- The original cloning of desmin complementary DNA clear interior (Capetanaki et al. 2007). Desmin is very im- (cDNA) (Capetanaki et al. 1984) has facilitated molecular portant for myogenic and cardiogenic differentiation. studies related to the gene encoding desmin and the role of Inhibition of desmin expression interferes not only with desmin protein in health and disease (Capetanaki et al. myoblast fusion and myotube differentiation but also 2015). Desmin is one of the earliest detected muscle-spe- with proper expression of the myogenic transcription reg- cific proteins during mammalian embryonic development ulators MyoD and myogenin in C2C12 cells (Li et al. 1994) Head Rod Tail 1A 1B 2A 2B 108 aa L1 L1/2 L2 54 aa DES 69 aa 55 aa GFAP 97 aa 63 aa PRPH 103 aa 55 aa VIM Figure 1. A schematic overview of the type III intermediate filaments (IFs) (only the human form is shown). The three IF domains—head, rod, and tail—are indicated. The rod domain is divided into subregions: the coiled-coil regions 1A (35 aa), 1B (8 aa), 2A (19 aa), and 2B (121 aa); and these subregions are separated by linker regions L1 (8 aa), L1/2 (DES, GFAP, and VIM, 16 aa; PRPH, 18 aa), and L2 (8 aa). The most variability in amino acid length is present in the head and tail region. aa, amino acids; DES, desmin; GFAP, glial fibrillary acidic protein; L, linker; PRPH, peripherin; VIM, vimentin. 2 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a021642 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Type III Intermediate Filaments and, additionally, of myf5 in desmin-deficient (des2/2) dria, lysosomes, and potentially the sarcoplasmic reticulum embryoid bodies (EBs) (Weitzeret al. 1995). Furthermore, (Capetanaki et al. 2007; Capetanaki et al. 2015). The mo- mutations of desmin interfere with cardiogenesis and lecular mechanism responsible for the majority of these are linked to down-regulation of brachyury, goosecoid, associations remains unknown. nkx2.5, and Mef2c, all important cardiogenic regulators (Hollrigl et al. 2002; Hofner et al. 2007; Hollrigl et al. 2.2.2 Links to Membranous Organelles 2007), whereas ectopic expression of desmin in embryonic stem cells promotes up-regulation of brachyury and nkx2.5 Desmin and the sarcolemma/intercalated disks (costamere (Hofner et al. 2007). All the above findings strongly suggest organization and function). Desmin IFs associate with the that the desmin cytoskeleton facilitates commitment of sarcolemma of both cardiac and skeletal muscle at struc- primitive mesoderm to cardiogenic and myogenic lineages tures termed “costameres,” present at the membrane over- or the maintenance of the committed lineages and subse- lying Z-disks. In addition, in cardiac muscle, desmin quent differentiation, as well as maintenance of proper associates with the desmosomes of the intercalated disks skeletal and cardiac muscle homeostasis and regeneration through desmoplakin (Capetanaki et al. 2015). Studies in adulthood. with desmin-deficient mice have shown that desmin IFs How could desmin be involved in these processes? As play an important role in stabilizing the organization of discussed above, it could act as the mechanosensor and the sarcolemma into costameres (O’Neill et al. 2002; Cape- transducer of mechanical forces to the nucleus, a hypoth- tanaki et al. 2007). esis supported by studies demonstrating that nuclear shape Desmin links to nuclei/mechanochemical signaling. Al- and positioning, as well as links to sarcomeres, are altered in though the nuclear envelope seems to isolate the cytoplas- desmin-null mice (Capetanaki et al. 1997; Shah et al. 2004; mic from the nuclear IF scaffold, these two systems form a Ralston et al. 2006), whereas lamin A/C–deficient cardio- continuous network, either directly through the nuclear myocytes show detachment of desmin IFs from the nuclear pores (Capetanaki et al. 2007; Capetanaki et al. 2015) or surface and progressive disruption of its network (Nikolova through the association of the cytoskeletal cross-linking et al. 2004). In addition, lamin A/C and emerin (Adam protein plectin and the LINC-complex protein nesprin 3. 2016) are crucial for skeletal muscle satellite cell differen- This association provides linkages between cytoskeletal IFs tiation, and restoration of normal desmin levels in and lamins A/C and the nuclear envelope protein emerin LmnA2/2 myoblasts enhances their differentiation poten- through interactions with SUN1 and SUN2 proteins (Wil- tial (Frock et al. 2006). Finally, very recent novel data have helmsen et al. 2005). These interactions are consistent with shown that desmin enters transiently the nucleus of cardiac the importance of desmin shown in the proper localization stem cells, physically interacts with transcription factor of myofiber nuclei (Ralston et al. 2006), the mechanical complexes bound to the enhancer and promoter elements coupling of the contractile apparatus and the nucleus of the Nkx2.5 gene, and regulates its transcription (Fuchs (Shah et al. 2004), and, consequently, the lamin-based nu- et al. 2016). cleoskeleton. Based on these findings, it has been proposed that the
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