2013 Group 5 Project

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2013 Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7

The Nuclear Envelope During Cell Division

Introduction

Nuclear Envelope and its Proteins

The nuclear envelope is a highly specialised membrane that outlines the nucleus [1] and is a key physical compartment that defines eukaryotic cells. Hetzer’s review (2010) describes it as a highly organised and regulated double membrane that compartmentalises the cell’s genome. [2]

It is composed of two concentric membranes, the outer nuclear membrane and the inner nuclear membrane, which are joined by Nuclear Pore Complexes (NPC) that span both membranes. [3] The outer membrane is continuous with the membrane of the Rough Endoplasmic Reticulum (rER), [4] while the inner membrane is attached to the lamina (directly beneath the inner membrane) and chromatin of the nucleus. [3]

The nuclear envelope serves to maintain the structure of the nucleus and its position in the cell by providing anchoring sites for its attachment to the cell’s cytoskeleton. [3] More importantly it serves to separate nuclear and cytoplasmic activities,[5] including transcription from translation, protecting genetic material from the highly metabolic environment of the cytoplasm. [6] It acts as a selective barrier between the cytoplasm and nuclear contents, with the NPCs contributing to this diffusion barrier by regulating the passage of proteins, RNA and ribonuleoprotein complexes in and out of the nucleus. [7] In addition, Hetzer’s has pointed out in his review article (2010) that more recent studies have shown the inner membrane proteins to play various important roles in the function of the nucleus including chromatin organization, gene expression and DNA metabolism. [2]

Changes to the nuclear envelope’s structure occur at the onset of mitosis, these changes are very slight in lower eukaryotes and in vertebrate cells result in the complete disassembly of the nuclear membrane, [8] this complete or partial breakdown is necessary in order to form the mitotic spindle on condensed chromosomes. [7] Higher eukaryotes must consequently reassemble nuclear envelopes round the genetic material of the daughter cells each time a cell divides in order to re-establish the nuclear compartment. [2] This page aims to explore the process of the breakdown and reassembly of the nuclear envelope and its role in cell division.

Historical Background

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]

It is thought that these transmemberane proteins direct the chromatin to the membrane; this is essential during the reformation of the NE after mitosis. [19] Furthermore, important intermediate proteins called lamins are attached with one another to form 10nm-diameter filaments and these lamins make up an important network called the nuclear lamina. This structure, the Nuclear Lamina, is important because it not only supplies rigidity to the nucleus but also has other roles in the cell [20] [21] Ulbert et al.(2006), through their research on transmemberane proteins, have illustrated that interaction of Lem2 with chromatin or lamins are crucial to the maintenance of NE. Ulbert et al. (2006) have also demonstrated that (from the interaction of Lem2 and its partners) that this transmemberane protein has an essential function in the structural integrity of NE . Furthermore, a reduction in the transmemberane protein leads to aggregation of cells with deformed nuclei and ultimately cell death. [22]


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 Mitosis

Mitotic Functions of Nuclear Envelope Components

Reformation of the Nuclear Envelope

Remodeling of the Nuclear Envelope During Interphase

Open vs. Closed/Semi-closed Mitosis

Mitosis is the process by which eukaryotic cells divide to form two equal daughter cells each with a copy of its genome. [31] 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. [32] 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. [31] Open mitosis is so named because the nuclear envelope completely breaks down at the transition from G2 to M stage of the cell cycle [32] and the nuclear content, including the genetic material, is “open” to mix with cytoplasmic macromolecules [33] until the nuclear envelope is reassembled after chromosomal segregation during telophase/G1. [32] [33] 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. [31]

However, classification of mitosis in eukaryotes into open or closed forms can be limiting as some organisms have been found to have varying extents of nuclear envelope breakdown and the timing of the breakdown can also be atypical of open mitosis. [31] [32] For example, a study conducted by Paddy et.al. (1996) on early Drosophila embryos, using time-resolved 3D fluorescence light microscopy imaging, showed that there was an abnormally long period during mitosis where a large fraction of lamins remained intact and localised around the periphery of the nucleus. This semi-disassembled envelope persisted long into metaphase spindle formation and eventually the lamins dispersed just before chromosomal segregation. They also observed an extensive series of structural rearrangements in the lamina which appeared to be linked to or driven by the movements of chromosomes and spindle microtubules. Paddy and peers (1996) state that this behaviour isn’t characteristic of neither open nor closed mitosis but instead appears to be of an intermediate form, [34] one of semi-open mitosis until after metaphase. [31]

In open mitosis the entire nuclear envelope, including the NPCs, breakdown allowing the formation of the spindles on the chromosomes [5] as well as their interaction with cytoplasmic macromolecules needed for mitosis. This means that the transport of molecules in and out of the nucleus through NPCs is not required during open mitosis. [35] In contrast, the nuclear envelope of eukaryotes undergoing closed mitosis remains intact, with the continual function of its NPCs that are important in maintaining the connection between the nucleus and cytoplasm so that tubulin and proteins, that are necessary for the regulation of entry into mitosis, are allowed to enter the nucleus. [32]

Abnormalities in Nuclear Envelope Breakdown and Reformation

Current and Future Research

Mislocalization of nuclear and cytoplasmic components.jpeg

Mislocalization of nuclear and cytoplasmic components

Glossary

Chromatin:

Lamina: a dense network of fibres composed of intermediate filaments made up of lamin proteins and lamin-associated proteins [36]

Nuclear Pore Complex (NPC): Very large protein complexes spanning through the outer nuclear and inner nuclear membranes creating gated channels that allow for transport of substances between the cytoplasm and nucleus [37]

Ribonuleoprotein complexes:

Rough Endoplasmic Reticulum (rER):

Images

References

  1. <pubmed>16389459</pubmed>
  2. 2.0 2.1 2.2 <pubmed>PMC2829960</pubmed>
  3. 3.0 3.1 3.2 <pubmed>16212499</pubmed>
  4. <pubmed>PMC2223813</pubmed>
  5. 5.0 5.1 <pubmed>PMC3501164</pubmed>
  6. Evans D, Hutchison C & Bryant J (2004) The Nuclear Envelope, Garland Science/BIOS Scientific Publishers, New York
  7. 7.0 7.1 <pubmed>PMC35011640</pubmed>
  8. <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 31.2 31.3 31.4 <pubmed>PMC2829850</pubmed>
  32. 32.0 32.1 32.2 32.3 32.4 <pubmed>PMC2043359</pubmed>
  33. 33.0 33.1 <pubmed>22064471</pubmed>
  34. <pubmed>8907705</pubmed>
  35. <pubmed>PMC2173375</pubmed>
  36. <pubmed>16389459</pubmed>
  37. <pubmed>16212499</pubmed>



2013 Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7

Dr Mark Hill 2013, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G