Stewart Mouse Models of the Nuclear Envelopathies and Related Diseases

1. Auflage 2014
ISBN: 978-0-12-398464-7
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 109, 352 Seiten

Reihe: Current Topics in Developmental Biology

Volume 109 of Current Topics in Developmental Biology covers mouse models of the nuclear envelopathies and related diseases, with contributions from an international board of authors. The chapters provide a comprehensive set of reviews covering such topics as mouse models neurodegenerative diseases including Parkinson's and dystonia, muscle ageing and sarcopenia, cardiac failure and repair, ageing and prospects lifespan extension, lipodystrophy and the significance in fat regulation, also identifying developmental mutations in mammals and nuclear envelope and LINC complex in disease. - Covers the area of mouse models of developmental genetic disease - International board of authors - Provides a comprehensive set of reviews covering such topics as mouse models neurodegenerative diseases including Parkinson's, muscle aging, lipodystrophy, and more

Autoren/Hrsg.

Stewart, Colin

Leseproben

Chapter One Functional Architecture of the Cell's Nucleus in Development, Aging, and Disease
Brian Burke*; Colin L. Stewart†,1    * Nuclear Dynamics and Architecture Group, Institute of Medical Biology, Immunos, Singapore, Singapore
† Development and Regenerative Biology Group, Institute of Medical Biology, Immunos, Singapore, Singapore
1 Corresponding author: email address: [e-mail] Abstract
In eukaryotes, the function of the cell's nucleus has primarily been considered to be the repository for the organism's genome. However, this rather simplistic view is undergoing a major shift, as it is increasingly apparent that the nucleus has functions extending beyond being a mere genome container. Recent findings have revealed that the structural composition of the nucleus changes during development and that many of these components exhibit cell- and tissue-specific differences. Increasing evidence is pointing to the nucleus being integral to the function of the interphase cytoskeleton, with changes to nuclear structural proteins having ramifications affecting cytoskeletal organization and the cell's interactions with the extracellular environment. Many of these functions originate at the nuclear periphery, comprising the nuclear envelope (NE) and underlying lamina. Together, they may act as a “hub” in integrating cellular functions including chromatin organization, transcriptional regulation, mechanosignaling, cytoskeletal organization, and signaling pathways. Interest in such an integral role has been largely stimulated by the discovery that many diseases and anomalies are caused by defects in proteins of the NE/lamina, the nuclear envelopathies, many of which, though rare, are providing insights into their more common variants that are some of the major issues of the twenty-first century public health. Here, we review the contributions that mouse mutants have made to our current understanding of the NE/lamina, their respective roles in disease and the use of mice in developing potential therapies for treating the diseases. Keywords Lamins Nuclear envelope Laminopathies Progeria LINC complex 1 Introduction
1.1 The nuclear envelope and lamina
In most eukaryotic cells, the nucleus is the most prominent organelle. The traditional view of the nucleus's function was that it served as the container for the cell's genome. Here, we discuss recent findings revealing that the nucleus has additional, nongenomic, functions that go beyond being the genome repository and impact on the whole cell, particularly cytoskeletal organization and function. When these functions breakdown this often leads to disease. Due to improved imaging techniques, it is apparent that the nucleus is not a homogeneous structure, and there is substantial subnuclear organization (Bickmore, 2013). Such organization, besides the nucleolus, includes nuclear structures such as Gems, Paraspeckles, PML bodies, and Cajal bodies, all involved in RNA processing (Mao, Zhang, & Spector, 2011). Furthermore, chromosomes are organized into distinct territories, with their chromatin being distributed into the tightly packed, densely staining heterochromatin at the nuclear periphery and around the nucleolus, and the more loosely packed lighter staining euchromatin occupying the rest of the nucleus (Cremer & Cremer, 2010). The structural organization of chromatin, with regard to its role in regulating gene expression, is currently an area of intense investigation. Enclosing all these structures is the nuclear envelope (NE). The envelope was originally thought to largely function as a selective barrier regulating the entry and exit of macromolecules via the nuclear pores. This view is changing. Increasing evidence is revealing that in addition to regulating nuclear transport, the NE acts as a cellular “hub” integrating many cellular functions including chromatin organization, signaling pathways, transcriptional regulation, and cytoskeletal organization (Dauer & Worman, 2009; Gruenbaum, Margalit, Goldman, Shumaker, & Wilson, 2005). The NE consists of the inner and outer nuclear membranes (INM and ONM, respectively) that are separated by the 40–50-nm diameter perinuclear space (PNS). Both membranes connect with each other where they are traversed by the nuclear pore complexes (NPCs) (Grossman, Medalia, & Zwerger, 2012). Since the ONM also connects at multiple points with the cytoplasmic endoplasmic reticulum (ER), this makes the ER, INM, and ONM one continuous membrane system with lumen of the ER being contiguous with the PNS (Stewart, Roux, & Burke, 2007). Despite the INM, ONM, and ER being one continuous system, each membrane is characterized by its’ association with a unique set of proteins. For instance, the peripheral ER contains the reticulon and DP1/Yop1p families of proteins that are required for the ER's assembly and maintenance as a tubular structure (Shnyrova, Frolov, & Zimmerberg, 2008). Both the ONM and ER, but not the INM, are associated with ribosomes. In contrast to the ONM and ER, proteomic studies have identified at least 70 transmembrane proteins that are found in the INM, some of which have already been extensively characterized (see below) and many that vary significantly in their expression between different cell types (Korfali et al., 2012; Schirmer, Florens, Guan, Yates, & Gerace, 2003). In metazoans, another component of the nuclear periphery is the lamina that underlies the INM (Dwyer & Blobel, 1976; Fig. 1.1). The nuclear lamina is a thin proteinaceous meshwork, which in most cells is some 10–20 nm thick, although the thickness can significantly increase in different cell types (Hoger, Grund, Franke, & Krohne, 1991). The principal components of the lamina are the type V intermediate filament proteins—the lamins, which are found exclusively in the nucleus (Gerace & Huber, 2012). The lamins consist of a central a-helical rod domain flanked by a head and tail globular domain (Fisher, Chaudhary, & Blobel, 1986; McKeon, Kirschner, & Caput, 1986). The large carboxy-terminal globular domain of about 200–300 amino acid residues has at its core an immunoglobulin (Ig)-like ß-fold, together as well as a nuclear localization sequence (Dhe-Paganon, Werner, Chi, & Shoelson, 2002; Krimm et al., 2002). In mammals, the lamins are grouped into two classes, A- (A, A?10, and C) and the B-types (B1, B2, and B3) (Peter et al., 1989; Vorburger, Lehner, Kitten, Eppenberger, & Nigg, 1989). Most adult mammalian somatic cells contain four major lamin proteins, A, B1, B2, and C. A single gene, LMNA, encodes the A-type lamins, which are generated by alternate splicing of a common pre-mRNA (Lin & Worman, 1993, 1995; Machiels et al., 1996). A minor spiced LMNA variant, lamin C2, is also produced in the testis (Furukawa, Inagaki, & Hotta, 1994). In mammals, most cells express the A-type lamins, both lamin A and C proteins at roughly equimolar amounts. However, in neurons of the central nervous system (CNS) lamin A protein is largely absent due translational inhibition by the microRNA (miR-9) that that binds to the 3' end of the longer lamin A transcript, and not to the shorter lamin C transcript (Jung, Tu, et al., 2014). Separate genes encode lamins B1 and B2 with lamin B3 being produced as a minor spliced variant of lamin B2 and as with lamin C2 is found in the testis (Furukawa & Hotta, 1993; Lin & Worman, 1995). Figure 1.1 The nuclear envelope (NE), lamina, and some of the more extensively characterized proteins associated with the lamina and NE. Panel A shows an electron micrograph of isolated rat liver NEs. The NE consists of the contiguous inner and outer nuclear membranes (INM and ONM, respectively), which are connected where the nuclear pore complexes traverse the two membranes. The arrows show the location of nuclear pore complexes. The red (dark gray in print) arrowheads indicate immunogold-labeled antibodies to lamin A decorating the underside of the INM. Panel B is a diagram of the NE/lamina with the localization of some on the proteins associated with the NE. Underlying the inner nuclear membrane is the 20–50-nm thick lamina, comprised of the lamins. Associated with the ONM, INM, and lamina are various proteins, with many connecting the INM to chromatin and DNA, for example, BAF and HP1. Panel C illustrates the structures of the mammalian lamins consisting of a central rod domain flanked at either end by globular domains. Only lamin A undergoes a second proteolytic cleavage step (P2) that removes the farnesylated cysteine. P, protease cleavage site; NLS, nuclear localization sequence. During translational processing, lamins A, B1, and B2 undergo a series of sequential modifications (Fig. 1.2). At the C-termini of lamin A and both the B-type lamins is a CaaX motif (where “C” is cysteine, “a” is an aliphatic amino acid, and “X” can be many different amino acids, although usually is a Met) that undergoes farnesylation and carboxy methylation. C-terminal processing of...