2013 Group 5 Project

From CellBiology


The Nuclear Envelope During Cell Division


Nuclear Envelope and its Proteins





Historical Background

Brief Timeline of Historical Research On The Nuclear Envelope

Time Discovery



Structure of the Nuclear Envelope

The nuclear envelope (NE) is an important structure that covers the nucleus with a double membrane. The prominent constituents of the NE include the nuclear lamina, nuclear pore complexes (NPCs) and nuclear membranes [9] . The nuclear membrane is made up of distinctive but unified domains: the outer nuclear membrane and the inner nuclear membrane [10] It is the small pore membranes that join the INM with the outer ONM together and the double membrane is separated by an intermembrane space. Moreover, the NE forms a partition between the nucleus and the cytoplasm and also allows attachment sites for structures such as the cytoskeleton to the nuclear periphery [11] [12]

Outer Nuclear Membrane

Structurally Continuous with and comparable in composition to the peripheral endoplasmic reticulum is the outer nuclear membrane. [13] [14]

Inner Nuclear Membrane

The Inner Nuclear membrane (INM), neighbouring with the endoplasmic reticulum membrane, is connected with the lamina and the chromatin [15]. It is in close contact with the genetic material of the nucleus and has various proteins attached to it. These proteins are manufactured on the rough endoplasmic reticulum and have important implication in human diseases which will be discussed later. [16] In recent years there has been an increase in the number of discoveries of various INM proteins mainlydue to the proteomic and computational approaches. [17] One such group of proteins include transmembrane proteins that are associated with the INM and they usually interact with chromatin and/or lamina. [18]


Nuclear Lamina

Nuclear Pore Complexes

One of the most essential components of the NE are the Nuclear Pore Complexes (NPCs) which are embedded in the nuclear envelope and they are necessary for proper cell functioning since they control the entrance and exit of macromolecules between the nucleus to the cytoplasm. [23] [24] The NPCs are composed of numerous copies of ~30 nucleoporins and span the nuclear envelope at junctions of the inner and outer nuclear membranes. [25] [26] The NPC has an estimate mass of 125MD in vertebrates and in a yeast, the NPC is found to have approximately 100nm ringed-shaped diameter. The NPC also has a central channel that is about 30nm in diameter. [27]

Moreover, as reviewed in DeGrasse et al. (2009), the NPC in eukaryotes have eight spokes around the central tube which serves as the medium for the bidirectional movement of macromolecules. [28] As reviewed in Akey (1985), it is thought that the NPCs have structural plasticity as its flexible nuclear pore diameter assists with the movement of specific macromolecules. [29]

Dynamical model of a NPC and NE system.png

Figure 1. Schematic view of model adopted for the NPC/NE system[30]

The Nuclear Envelope At the Onset of Mitosis

Breakdown of the Nuclear Envelope

Nuclear Envelope Breakdown and Reassembly During Open Mitosis

The breakdown of the nuclear envelope only occurs in higher eukaryotes/metazoans like plants and animals. The entry of a cell into mitosis (prophase) is defined by this loss of compartmentalisation of the nuclear content [2] and it not only involves the removal of the inner and outer nuclear membranes but also the disassembly of the underlying lamina and NPCs. [31] These organisms form spindle microtubules which are located in the cytoplasm and are vital in mitosis for the segregation of chromosomes, therefore the disassembly of the nuclear envelope is required in order for these microtubules to gain access to the kinetochores of the chromosomes. [31]

Reviews by Kutay and Hetzer (2008) describe the breakdown of the nuclear envelope as involving three key processes: the disassembly of NPCs and the subsequent increase in nuclear envelope permeability, the depolymerisation and consequent breakdown of the nuclear lamina and then the disassociation of the nuclear envelope from the chromatin. [8]

The Disassembly of the Nuclear Pore Complexes


It has been observed that this process is very rapid in living mammalian cells [33] and removes the permeability barrier of the nuclear envelope resulting in the mixing of nuclear and cytoplasmic components. [34] Studies of living mammalian cells and starfish oocytes reveal that the first Nups to clearly disassociate from the NPCs is Nup98. [33] [35] Nup98 is a peripheral nucleoporin that is found symmetrically on both sides of the NPC with GLFG-type FG repeats that are thought to be important in the formation of the NPC permeability barrier. [34]

The Depolymerisation of the Nuclear Lamina

The Disassociation of the Nuclear Envelope From Chromatin

The Dispersal of Nuclear Envelope Components into the Endoplasmic Reticulum

Mitotic Functions of Nuclear Envelope Components

Reformation of the Nuclear Envelope

Remodeling of the Nuclear Envelope During Interphase

Open vs. Closed/Semi-closed Mitosis

Open and Closed Mitosis and Virtual Nuclear Envelope Breakdown

Mitosis is the process by which eukaryotic cells divide to form two equal daughter cells each with a copy of its genome. [36] Typically eukaryotic cells undergo one of the two forms of mitosis; higher eukaryotes (metazoans) go through Open Mitosis, while lower eukaryotes including yeast and other types of fungi undergo Closed Mitosis. [37] The distinction between open and closed mitosis can be made by focusing on the behaviour of the nuclear envelope which separates the nuclear contents from the cytoplasm and is split to form daughter nuclei. [36] Open mitosis is so named because the nuclear envelope completely breaks down at the transition from G2 to M stage of the cell cycle [37] and the nuclear content, including the genetic material, is “open” to mix with cytoplasmic macromolecules [38] until the nuclear envelope is reassembled after chromosomal segregation during telophase/G1. [37] [38] In contrast, during closed mitosis the nuclear envelope remains intact and mitosis continues within the nucleus resulting in the fission of the nuclear envelope after chromosomal segregation. [36]



The importance of the maintenance of the NPCs in closed mitosis is evident in a study conducted by Louk et.al (2002) where fluorescent microscopy was used to analyse the nuclear envelope and NPCs of the yeast Saccharomyces cerevisiae. They found a link between components of yeast NPCs and the mitotic checkpoint machinery, showing that the Mad1p and Mad2p proteins, required for the establishment of the spindle checkpoint, were mostly found at NPCs throughout the cell cycle. These proteins were previously found to be associated with nucleoporin sub-complexes made up of Nup53p, Nup59p and Nup170p. Further investigation conducted in this study showed that the association of Mad proteins with NPCs particularly required Mad1p and that Nup53p was responsible for ensuring the connection between the Mad1p-Mad2p complex and the NPCs. They observed that once the spindle checkpoint was activated, a build up of Mad2p at the kinetochores occurred which coincided with the hyperphosphorylation of Mad1p mediated by Nup53. These observations led Louk and his peers to suggest a model where the association of Mad1p to Nup53p-containing NPCs traps Mad2p until it is primed for release by the spindle checkpoint activation. In addition they suggest that the bond between Nup53p and Mad1p has a role in the aid of transport through the nuclear envelope. [41]

Abnormalities in Nuclear Envelope Breakdown and Reformation

Current and Future Research

Mislocalization of nuclear and cytoplasmic components.jpeg

Mislocalization of nuclear and cytoplasmic components





Ribonuleoprotein complexes:

Rough Endoplasmic Reticulum (rER):



  1. <pubmed>16389459</pubmed>
  2. 2.0 2.1 2.2 2.3 2.4 <pubmed>PMC2829960</pubmed>
  4. <pubmed>PMC2223813</pubmed>
  5. 5.0 5.1 <pubmed>PMC3501164</pubmed>
  7. 7.0 7.1 <pubmed>PMC35011640</pubmed>
  8. 8.0 8.1 <pubmed>PMC2713602</pubmed>
  9. <pubmed>3501164</pubmed>
  10. <pubmed>22863006</pubmed>
  11. <pubmed>22863006</pubmed>
  12. <pubmed>9182656 </pubmed>
  13. <pubmed>22307332</pubmed>
  14. <pubmed>22863006 </pubmed>
  15. <pubmed>11593002</pubmed>
  16. <pubmed>21518795</pubmed>
  17. <pubmed>17097643</pubmed>
  18. <pubmed>17097643</pubmed>
  19. <pubmed>17097643</pubmed>
  20. <pubmed>19720741</pubmed>
  21. <pubmed>19730674</pubmed>
  22. <pubmed>17097643</pubmed>
  23. <pubmed>11593002</pubmed>
  24. <pubmed>2742445</pubmed>
  25. <pubmed>1973067</pubmed>
  26. <pubmed>3431207</pubmed>
  27. <pubmed>19730674</pubmed>
  28. <pubmed>19525551</pubmed>
  29. <pubmed>7739040</pubmed>
  30. <pubmed>19730674</pubmed>
  31. 31.0 31.1 <pubmed>19234477</pubmed>
  32. <pubmed>21636979</pubmed>
  33. 33.0 33.1 <pubmed>PMC2265396</pubmed>
  34. 34.0 34.1 <pubmed>21335236</pubmed>
  35. <pubmed>PMC2172766</pubmed>
  36. 36.0 36.1 36.2 36.3 36.4 <pubmed>PMC2829850</pubmed>
  37. 37.0 37.1 37.2 37.3 37.4 <pubmed>PMC2043359</pubmed>
  38. 38.0 38.1 <pubmed>22064471</pubmed>
  39. <pubmed>8907705</pubmed>
  40. <pubmed>PMC2173375</pubmed>
  41. <pubmed>12473689</pubmed>
  42. <pubmed>16389459</pubmed>
  43. <pubmed>16212499</pubmed>

