Cell nuclei, the most conspicuous organelles of eukaryotic cells, came first into view around 1830, when Robert Brown described areola within plant cells, which he called nuclei. Descriptions of nuclei in cells of different origin, of nucleoli and of other subnuclear structures like Cajal bodies followed, and, soon, nuclei were recognized as the structure containing the genetic material of the cell.
Since the early days of microscopy, our view of the nucleus has developed dramatically. It changed from a rather static picture into a vivid one of a highly dynamic cellular center for processing genetic information, organizing gene expression in all its facettes. It depicts many macromolecules moving rapidly throughout nuclear space, building complexes rather on the fly, which finally coalesce into nuclear bodies at yet ill-defined molecular organizing-centers. The scene for this molecular ballet is set by the chromosomes which, being far from static themselves, nevertheless do not mix but occupy their individual chromosome territories. They build the nuclear space, whose boundaries are formed by the nuclear envelope.

Structural organization of the nuclear envelope

The nuclear envelope separates the nuclear space from the cytoplasm. Its two membranes, both part of the endoplasmic reticulum (ER), enclose the perinuclear space of the ER lumen and are interconnected at the nuclear pores. The outer nuclear membrane (ONM) connects the nuclear membranes to the remainder of the ER membranes. It shows the characteristics of the rough ER and is involved in the synthesis of membrane and secretory proteins. The inner nuclear membrane (INM), in contrast, is a domain distinct from ER with a unique set of membrane proteins attaching the nuclear membranes to the intermediate filaments of the lamina and to chromatin. Remarkably, beneath the INM and the lamina it has mostly adopted the compact state of heterochromatin. The high-affinity association of specific INM proteins with the meshwork of the lamin filaments conveys a high degree of stability to the nuclear envelope (Gant and Wilson, 1997).

Integrated into lamina and nuclear membranes, the protein assemblies of the nuclear pore complexes occupy the nuclear pores. They connect nucleoplasm and cytoplasm and control an elaboratedly regulated nucleocytoplasmic exchange of both high-molecular-weight proteins and ribonucleoprotein particles up to the size of fully assembled large ribosomal-subunits (Fahrenkrog and Aebi, 2003).

The nuclear envelope is highly dynamic

Despite being a highly stable, seemingly static structure, the nuclear envelope responds dynamically to cellular requirements. For example, it grows and shrinks in response to changes in the nuclear space, allows the de novo insertion of nuclear pore complexes, when a high flow of macromolecules between nucleus and cytoplasm has to be sustained, and, in higher eukaryotes, disassembles and reassembles in the course of mitosis. At the beginning of mitosis, the nuclear membranes lose their integrity, detach from lamins and chromatin, and mix with the other ER membranes. The lamina loses its contact to chromatin and INM and dissolves, which is achieved by phosphorylation of lamins and other nuclear-envelope proteins at only a few phosphorylation sites (Lenart and Ellenberg, 2003).

Many more NE proteins await their discovery

The identification of new nuclear-envelope proteins (Dreger et al., 2001; Schirmer et al., 2003), the elucidation of the nucleocytoplasmic-transport mechanisms, and the comprehensive characterization of yeast and mammalian nuclear pore complexes (Cronshaw et al., 2002; Rout et al., 2000) have considerably expanded our knowledge about the nuclear envelope. Our knowledge of the molecular composition of the nuclear membranes let alone their molecular interactions seems, however, still rather limited.

By its high-affinity binding to lamins, the lamin B receptor (LBR) as the first example of an integral INM protein has been discovered in 1988. Today, approximately 20 different membrane proteins of the nuclear envelope, some of which come in different isoforms, have been confirmed (Dreger et al., 2001; Schirmer et al., 2003). Yet their interactions with other nuclear macromolecules are for all but a very few exceptions largely unknown. For the best-characterized INM proteins, the LBR and the lamina-associated polypeptide 2 (LAP 2), binding to heterochromatin proteins and to transcription regulators has been shown, and, by interfering with the endogenous proteins, they have been functionally linked to transcription or DNA replication (reviewed in Mattout-Drubezki and Gruenbaum, 2003). For other nuclear membrane proteins, however, only their targeting to the nuclear rim has been demonstrated.

Laminopathies are NE dysfuction diseases

The significance of molecular interactions at the nuclear envelope has been convincingly demonstrated by the identification of severe genetic diseases linked to lamin A and to INM proteins (Mounkes et al., 2003). The first of these so-called laminopathies was the Emery–Dreifuss muscle dystrophy caused by mutations in either lamin A or the INM-protein emerin, which result in the lack of either protein or in disturbed interactions between both proteins. Since then, at least 7 different dystrophies have been linked to alterations in the lamin A gene, the latest being the Hutchinson–Gilford Progeria Syndrome (HGPS). Other INM proteins may also be affected by pathologic mutations. The Pelger–Huet anomaly, for example, is a severe genetic condition linked to knockdown of the LBR (Hoffmann et al., 2002). We should therefore expect to see emerging other diseases based on yet unknown nuclear envelope proteins.

References

modified from Otto, "The nuclear-envelope jigsaw puzzle", Zellbiologie aktuell 30 (2004) 15-18

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Henning Otto / updated: 12.04.2011