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In cell biology, the nucleus (pl. nuclei; from Latin Error: {{Lang}}: text has italic markup (help) or Error: {{Lang}}: text has italic markup (help), kernel) is a membrane-enclosed organelle found in most eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these chromosomes make up the cell's nuclear genome. The function of the nucleus is to maintain the integrity of these genes and to control the activities of the cell by regulating gene expression.

The main structural elements of the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and keeps its contents separated from the cellular cytoplasm, and the nuclear lamina, a meshwork within the nucleus that adds mechanical support much like the cytoskeleton supports the cell as a whole. Because the nuclear membrane is impermeable to most molecules, nuclear pores are required to allow movement of molecules across the envelope. These pores cross both membranes of the envelope, providing a channel that allows free movement of small molecules and ions. The movement of larger molecules such as proteins is carefully controlled, and requires active transport facilitated by carrier proteins. Nuclear transport is of paramount importance to cell function, as movement through the pores is required for both gene expression and chromosomal maintenance.

Although the interior of the nucleus does not contain any membrane-delineated bodies, its contents are not uniform, and a number of subnuclear bodies exist, made up of unique proteins, RNA molecules, and DNA conglomerates. The best known of these is the nucleolus, which is mainly involved in assembly of ribosomes. After being produced in the nucleolus, ribosomes are exported to the cytoplasm where they translate mRNA.

History

The nucleus was the first organelle to be discovered, and was first described by Franz Bauer in 1802. It was later described in more detail by Scottish botanist Robert Brown in 1831 in a talk at the Linnean Society of London. Brown was studying orchids microscopically when he observed an opaque area, which he called the areola or nucleus, in the cells of the flower's outer layer. He did not suggest a potential function. In 1838 Matthias Schleiden proposed that the nucleus plays a role in generating cells, thus he introduced the name "Cytoblast" (cell builder). He believed that he had observed new cells assembling around "cytoblasts". Franz Meyen was a strong opponent of this view having already described cells multiplying by division and believing that many cells would have no nuclei. The idea that cells can be generated de novo, by the "cytoblast" or otherwise, contradicted work by Robert Remak (1852) and Rudolf Virchow (1855) who decisively propagated the new paradigm that cells are generated solely by cells ("Omnis cellula e cellula"). The function of the nucleus remained unclear.

Between 1876 and 1878 Oscar Hertwig published several studies on the fertilization of sea urchin eggs, showing that the nucleus of the sperm enters the oocyte and fuses with its nucleus. This was the first time it was suggested that an individual develops from a (single) nucleated cell. This was in contradiction to Ernst Haeckel's theory that the complete phylogeny of a species would be repeated during embryonic development, including generation of the first nucleated cell from a "Monerula", a structureless mass of primordial mucus ("Urschleim"). Therefore, the necessity of the sperm nucleus for fertilization was discussed for quite some time. However, Hertwig confirmed his observation in other animal groups, e.g. amphibians and molluscs. Eduard Strasburger produced the same results for plants (1884). This paved the way to assign the nucleus an important role in heredity. In 1873 August Weismann postulated the equivalence of the maternal and paternal germ cells for heredity. The function of the nucleus as carrier of genetic information became clear only later, after mitosis was discovered and the Mendelian rules were rediscovered at the beginning of the 20th century: the chromosome theory of heredity was developed.

Structure

The nucleus is the largest cellular organelle. In mammalian cells, the average diameter typically varies from 11 to 22 micrometers (μm) and occupies about 10% of the total volume. The viscous liquid within it is called nucleoplasm, and is similar to the cytoplasm found outside the nucleus.

Nuclear envelope and pores

The nuclear envelope consists of two cellular membranes, an inner and an outer membrane, arranged parallel to one another and separated by 10 to 50 nanometers (nm). The nuclear envelope completely encloses the nucleus and separates the cell's genetic material from the surrounding cytoplasm, serving as a barrier to prevent macromolecules from diffusing freely between the nucleoplasm and the cytoplasm. The outer nuclear membrane is continuous with the membrane of the rough endoplasmic reticulum (RER), and is similarly studded with ribosomes. The space between the membranes is called the perinuclear space and is continuous with the RER lumen.

Nuclear pores, which provide aqueous channels through the envelope, are composed of multiple proteins, collectively referred to as nucleoporins. The pores are about 125 million daltons in molecular weight and consist of around 50 (in yeast) to 100 proteins (in vertebrates). The pores are 100 nm in total diameter; however, the gap through which molecules freely diffuse is only about 9 nm wide, due to the presence of regulatory systems within the center of the pore. This size allows the free passage of small water-soluble molecules while preventing larger molecules, such as nucleic acids and proteins, from inappropriately entering or exiting the nucleus. These large molecules must be actively transported into the nucleus instead. The nucleus of a typical mammalian cell will have about 3000 to 4000 pores throughout its envelope, each of which contains a donut-shaped, eightfold-symmetric ring-shaped structure at a position where the inner and outer membranes fuse. Attached to the ring is a structure called the nuclear basket that extends into the nucleoplasm, and a series of filamentous extensions that reach into the cytoplasm. Both structures serve to mediate binding to nuclear transport proteins.

Most proteins, ribosomal subunits, and some RNAs are transported through the pore complexes in a process mediated by a family of transport factors known as karyopherins. Those karyopherins that mediate movement into the nucleus are also called importins, while those that mediate movement out of the nucleus are called exportins. Most karyopherins interact directly with their cargo, although some use adaptor proteins. Steroid hormones such as cortisol and aldosterone, as well as other small lipid-soluble molecules involved in intercellular signaling can diffuse through the cell membrane and into the cytoplasm, where they bind nuclear receptor proteins that are trafficked into the nucleus. There they serve as transcription factors when bound to their ligand; in the absence of ligand many such receptors function as histone deacetylases that repress gene expression.

Cytoskeleton

In animal cells, two networks of intermediate filaments provide the nucleus with mechanical support: the nuclear lamina forms an organized meshwork on the internal face of the envelope, while less organized support is provided on the cytosolic face of the envelope. Both systems provide structural support for the nuclear envelope and anchoring sites for chromosomes and nuclear pores.

The nuclear lamina is mostly composed of lamin proteins. Like all proteins, lamins are synthesized in the cytoplasm and later transported into the nucleus interior, where they are assembled before being incorporated into the existing network of nuclear lamina. Lamins are also found inside the nucleoplasm where they form another regular structure, known as the nucleoplasmic veil, that is visible using fluorescence microscopy. The actual function of the veil is not clear, although it is excluded from the nucleolus and is present during interphase. The lamin structures that make up the veil bind chromatin and disrupting their structure inhibits transcription of protein-coding genes.

Like the components of other intermediate filaments, the lamin monomer contains an alpha-helical domain used by two monomers to coil around each other, forming a dimer structure called a coiled coil. Two of these dimer structures then join side by side, in an antiparallel arrangement, to form a tetramer called a protofilament. Eight of these protofilaments form a lateral arrangement that is twisted to form a ropelike filament. These filaments can be assembled or disassembled in a dynamic manner, meaning that changes in the length of the filament depend on the competing rates of filament addition and removal.

Mutations in lamin genes leading to defects in filament assembly are known as laminopathies. The most notable laminopathy is the family of diseases known as progeria, which causes the appearance of premature aging in its sufferers. The exact mechanism by which the associated biochemical changes give rise to the aged phenotype is not well understood.

Chromosomes

The cell nucleus contains the majority of the cell's genetic material, in the form of multiple linear DNA molecules organized into structures called chromosomes. During most of the cell cycle these are organized in a DNA-protein complex known as chromatin, and during cell division the chromatin can be seen to form the well defined chromosomes familiar from a karyotype. A small fraction of the cell's genes are located instead in the mitochondria.

There are two types of chromatin. Euchromatin is the less compact DNA form, and contains genes that are frequently expressed by the cell. The other type, heterochromatin, is the more compact form, and contains DNA that are infrequently transcribed. This structure is further categorized into facultative heterochromatin, consisting of genes that are organized as heterochromatin only in certain cell types or at certain stages of development, and constitutive heterochromatin that consists of chromosome structural components such as telomeres and centromeres. During interphase the chromatin organizes itself into discrete individual patches, called chromosome territories. Active genes, which are generally found in the euchromatic region of the chromosome, tend to be located towards the chromosome's territory boundary.

Antibodies to certain types of chromatin organization, particularly nucleosomes, have been associated with a number of autoimmune diseases, such as systemic lupus erythematosus. These are known as anti-nuclear antibodies (ANA) and have also been observed in concert with multiple sclerosis as part of general immune system dysfunction. As in the case of progeria, the role played by the antibodies in inducing the symptoms of autoimmune diseases is not obvious.

Nucleolus

The nucleolus is a discrete densely-stained structure found in the nucleus. It is not surrounded by a membrane, and is sometimes called a suborganelle. It forms around tandem repeats of rDNA, DNA coding for ribosomal RNA (rRNA). These regions are called nucleolar organizer regions (NOR). The main roles of the nucleolus are to synthesize rRNA and assemble ribosomes. The structural cohesion of the nucleolus depends on its activity, as ribosomal assembly in the nucleolus results in the transient association of nucleolar components, facilitating further ribosomal assembly, and hence further association. This model is supported by observations that inactivation of rDNA results in intermingling of nucleolar structures.

The first step in ribosomal assembly is transcription of the rDNA, by a protein called RNA polymerase I, forming a large pre-rRNA precursor. This is cleaved into the subunits 5.8S, 18S, and 28S rRNA. The transcription, post-transcriptional processing, and assembly of rRNA occurs in the nucleolus, aided by small nucleolar RNA (snoRNA) molecules, some of which are derived from spliced introns from messenger RNAs encoding genes related to ribosomal function. The assembled ribosomal subunits are the largest structures passed through the nuclear pores.

When observed under the electron microscope, the nucleolus can be seen to consist of three distinguishable regions: the innermost fibrillar centers (FCs), surrounded by the dense fibrillar component (DFC), which in turn is bordered by the granular component (GC). Transcription of the rDNA occurs either in the FC or at the FC-DFC boundary, and therefore when rDNA transcription in the cell is increased more FCs are detected. Most of the cleavage and modification of rRNAs occurs in the DFC, while the latter steps involving protein assembly onto the ribosomal subunits occurs in the GC.

Other subnuclear bodies

Besides the nucleolus, the nucleus contains a number of other non-membrane delineated bodies. These include Cajal bodies, Gemini of coiled bodies, polymorphic interphase karyosomal association (PIKA), promyelocytic leukaemia (PML) bodies, paraspeckles and splicing speckles. Although little is known about a number of these domains, they are significant in that they show that the nucleoplasm is not uniform mixture, but rather contains organized functional subdomains.

Other subnuclear structures appear as part of abnormal disease processes. For example, the presence of small intranuclear rods have been reported in some cases of nemaline myopathy. This condition typically results from mutations in actin, and the rods themselves consist of mutant actin as well as other cytoskeletal proteins.

Cajal bodies and gems

A nucleus typically contains between 1 and 10 compact structures called Cajal bodies or coiled bodies (CB), whose diameter measures between 0.2 µm and 2.0 µm depending on the cell type and species. When seen under an electron microscope, they resemble balls of tangled thread and are dense foci of distribution for the protein coilin. CBs are involved in a number of different roles relating to RNA processing, specifically small nucleolar RNA (snoRNA) and small nuclear RNA (snRNA) maturation, and histone mRNA modification.

Similar to Cajal bodies are Gemini of coiled bodies, or gems, whose name is derived from the Gemini constellation in reference to their close "twin" relationship with CBs. Gems are similar in size and shape to CBs, and in fact are virtually indistinguishable under the microscope. Unlike CBs, gems don't contain small nuclear ribonucleoproteins (snRNPs), but do contain a protein called survivor of motor neurons (SMN) whose function relates to snRNP biogenesis. Gems are believed to assist CBs in snRNP biogenesis, though it has also been suggested from microscopy evidence that CBs and gems are different manifestations of the same structure.

PIKA and PTF domains

PIKA domains, or polymorphic interphase karyosomal associations, were first described in microscopy studies in 1991. Their function was and remains unclear, though they were not thought to be associated with active DNA replication, transcription, or RNA processing. They have been found to often associate with discrete domains defined by dense localization of the transcription factor PTF, which promotes transcription of snRNA.

PML bodies

Promyelocytic leukaemia bodies (PML bodies) are spherical bodies found scattered throughout the nucleoplasm, measuring around 0.2–1.0 µm. They are known by a number of other names, including nuclear domain 10 (ND10), Kremer bodies, and PML oncogenic domains. They are often seen in the nucleus in association with Cajal bodies and cleavage bodies. It has been suggested that they play a role in regulating transcription.

Paraspeckles

Discovered by Fox et al. in 2002, paraspeckles are irregularly shaped compartments in the nucleus' interchromatin space. First documented in HeLa cells, where there are generally 10–30 per nucleus, paraspeckles are now known to also exist in all human primary cells, transformed cell lines and tissue sections. Their name is derived from their distribution in the nucleus; the "para" is short for parallel and the "speckles" refers to the splicing speckles to which they are always in close proximity.

Paraspeckles are dynamic structures that are altered in response to changes in cellular metabolic activity. They are transcription dependent and in the absence of RNA Pol II transcription, the paraspeckle disappears and all of its associated protein components (PSP1, p54nrb, PSP2, CFI(m)68 and PSF) form a crescent shaped perinucleolar cap in the nucleolus. This phenomenon is demonstrated during the cell cycle. In the cell cycle, paraspeckles are present during interphase and during all of mitosis except for telophase. During telophase, when the two daughter nuclei are formed, there is no RNA Pol II transcription so the protein components instead form a perinucleolar cap.

Splicing speckles

Sometimes referred to as interchromatin granule clusters, speckles are rich in splicing snRNPs and other splicing proteins necessary for pre-mRNA processing. Because of a cell's changing requirements, the composition and location of these bodies changes according to mRNA transcription and regulation via phosphorylation of specific proteins.

Function

The main function of the cell nucleus is to control gene expression and mediate the replication of DNA during the cell cycle. The nucleus provides a site for genetic transcription that is segregated from the location of translation in the cytoplasm, allowing levels of gene regulation that are not available to prokaryotes.

Cell compartmentalization

The nuclear envelope allows the nucleus to control its contents, and separate them from the rest of the cytoplasm where necessary. This is important for controlling processes on either side of the nuclear membrane. In some cases where a cytoplasmic process needs to be restricted, a key participant is removed to the nucleus, where it interacts with transcription factors to downregulate the production of certain enzymes in the pathway. This regulatory mechanism occurs in the case of glycolysis, a cellular pathway for breaking down glucose to produce energy. Hexokinase is an enzyme responsible for the first the step of glycolysis, forming glucose-6-phosphate from glucose. At high concentrations of fructose-6-phosphate, a molecule made later from glucose-6-phosphate, a regulator protein removes hexokinase to the nucleus, where it forms a transcriptional repressor complex with nuclear proteins to reduce the expression of genes involved in glycolysis.

In order to control which genes are being transcribed, the cell separates some transcription factor proteins responsible for regulating gene expression from physical access to the DNA until they are activated by other signaling pathways. This prevents even low levels of inappropriate gene expression. For example in the case of NF-κB-controlled genes, which are involved in most inflammatory responses, transcription is induced in response to a signal pathway such as that initiated by the signaling molecule TNF-α, binds to a cell membrane receptor, resulting in the recruitment of signalling proteins, and eventually activating the transcription factor NF-κB. A nuclear localisation signal on the NF-κB protein allows it to be transported through the nuclear pore and into the nucleus, where it stimulates the transcription of the target genes.

The compartmentalization allows the cell to prevent translation of unspliced mRNA. Eukaryotic mRNA contains introns that must be removed before being translated to produce functional proteins. The splicing is done inside the nucleus before the mRNA can be accessed by ribosomes for translation. Without the nucleus ribosomes would translate newly transcribed (unprocessed) mRNA resulting in misformed and nonfunctional proteins.

Gene expression

Gene expression first involves transcription, in which DNA is used as a template to produce RNA. In the case of genes encoding proteins, that RNA produced from this process is messenger RNA (mRNA), which then needs to be translated by ribosomes to form a protein. As ribosomes are located outside the nucleus, mRNA produced needs to be exported.

Since the nucleus is the site of transcription, it also contains a variety of proteins which either directly mediate transcription or are involved in regulating the process. These proteins include helicases that unwind the double-stranded DNA molecule to facilitate access to it, RNA polymerases that synthesize the growing RNA molecule, topoisomerases that change the amount of supercoiling in DNA, helping it wind and unwind, as well as a large variety of transcription factors that regulate expression.

Processing of pre-mRNA

Newly synthesized mRNA molecules are known as primary transcripts or pre-mRNA. They must undergo post-transcriptional modification in the nucleus before being exported to the cytoplasm; mRNA that appears in the nucleus without these modifications is degraded rather than used for protein translation. The three main modifications are 5' capping, 3' polyadenylation, and RNA splicing. While in the nucleus, pre-mRNA is associated with a variety of proteins in complexes known as heterogeneous ribonucleoprotein particles (hnRNPs). Addition of the 5' cap occurs co-transcriptionally and is the first step in post-translational modification. The 3' poly-adenine tail is only added after transcription is complete.

RNA splicing, carried out by a complex called the spliceosome, is the process by which introns, or regions of DNA that do not code for protein, are removed from the pre-mRNA and the remaining exons connected to re-form a single continuous molecule. This process normally occurs after 5' capping and 3' polyadenylation but can begin before synthesis is complete in transcripts with many exons. Many pre-mRNAs, including those encoding antibodies, can be spliced in multiple ways to produce different mature mRNAs that encode different protein sequences. This process is known as alternative splicing, and allows production of a large variety of proteins from a limited amount of DNA.

Dynamics and regulation

Nuclear transport

The entry and exit of large molecules from the nucleus is tightly controlled by the nuclear pore complexes. Although small molecules can enter the nucleus without regulation, macromolecules such as RNA and proteins require association karyopherins called importins to enter the nucleus and exportins to exit. "Cargo" proteins that must be translocated from the cytoplasm to the nucleus contain short amino acid sequences known as nuclear localization signals which are bound by importins, while those transported from the nucleus to the cytoplasm carry nuclear export signals bound by exportins. The ability of importins and exportins to transport their cargo is regulated by GTPases, enzymes that hydrolyze the molecule guanosine triphosphate to release energy. The key GTPase in nuclear transport is Ran, which can bind either GTP or GDP (guanosine diphosphate) depending on whether it is located in the nucleus or the cytoplasm. Whereas importins depend on RanGTP to dissociate from their cargo, exportins require RanGTP in order to bind to their cargo.

Nuclear import depends on the importin binding its cargo in the cytoplasm and carrying it through the nuclear pore into the nucleus. Inside the nucleus, RanGTP acts to separate the cargo from the importin, allowing the importin to exit the nucleus and be reused. Nuclear export is similar, as the exportin binds the cargo inside the nucleus in a process facilitated by RanGTP, exits through the nuclear pore, and separates from its cargo in the cytoplasm.

Specialized export proteins exist for translocation of mature mRNA and tRNA to the cytoplasm after post-transcriptional modification is complete. This quality-control mechanism is important due to the these molecules' central role in protein translation; mis-expression of a protein due to incomplete excision of exons or mis-incorporation of amino acids could have negative consequences for the cell; thus incompletely modified RNA that reaches the cytoplasm is degraded rather than used in translation.

Assembly and disassembly

During its lifetime a nucleus may be broken down, either in the process of cell division or as a consequence of apoptosis, a regulated form of cell death. During these events, the structural components of the nucleus—the envelope and lamina—are systematically degraded.

During the cell cycle the cell divides to form two cells. In order for this process to be possible, each of the new daughter cells must have a full set of genes, a process requiring replication of the chromosomes as well as segregation of the separate sets. This occurs by the replicated chromosomes, the sister chromatids, attaching to microtubules, which in turn are attached to different centrosomes. The sister chromatids can then be pulled to separate locations in the cell. However, in many cells the centrosome is located in the cytoplasm, outside the nucleus, the microtubles would be unable to attach to the chromatids in the presence of the nuclear envelope. Therefore the early stages in the cell cycle, beginning in prophase and until around prometaphase, the nuclear membrane is dismantled. Likewise, during the same period, the nuclear lamina is also disassembled, a process regulated by phosphorylation of the lamins. Towards the end of the cell cycle, the nuclear membrane is reformed, and around the same time, the nuclear lamina are reassembled by dephosphorylating the lamins.

Apoptosis is a controlled process in which the cell's structural components are destroyed, resulting in death of the cell. Changes associated with apoptosis directly affect the nucleus and its contents, for example in the condensation of chromatin and the disintegration of the nuclear envelope and lamina. The destruction of the lamin networks is controlled by specialized apoptotic proteases called caspases, which cleave the lamin proteins and thus degrade the nucleus' structural integrity. Lamin cleavage is sometimes used as a laboratory indicator of caspase activity in assays for early apoptotic activity Cells that express mutant caspase-resistant lamins are deficient in nuclear changes related to apoptosis, suggesting that lamins play a role in initiating the events that lead to apoptotic degradation of the nucleus. Inhibition of lamin assembly itself is an inducer of apoptosis.

The nuclear envelope acts as a barrier that prevents both DNA and RNA viruses from entering the nucleus. Some viruses require access to proteins inside the nucleus in order to replicate and/or assemble. DNA viruses, such as herpesvirus replicate and assemble in the cell nucleus, and exit by budding through the inner nuclear membrane. This process is accompanied by disassembly of the lamina on the nuclear face of the inner membrane.

Anucleated and polynucleated cells

Although most cells have a single nucleus, some cell types have no nucleus, and others have many nuclei. This can be a normal process, as in the maturation of mammalian red blood cells, or an anomalous result of faulty cell division.

Anucleated cells contain no nucleus and are therefore incapable of dividing to produce daughter cells. The best-known anucleated cell is the mammalian red blood cell, or erythrocyte, which also lacks other organelles such as mitochondria and serves primarily as a transport vessel to ferry oxygen from the lungs to the body's tissues. Erythrocytes mature via erythropoiesis in the bone marrow, where they lose their nuclei, organelles, and ribosomes. The nucleus is expelled during the process of differentiation from an erythroblast to a reticulocyte, the immediate precursor of the mature erythrocyte. The presence of mutagens may induce the release of some immature "micronucleated" erythrocytes into the bloodstream. Anucleated cells can also arise from flawed cell division in which one daughter lacks a nucleus and the other is binucleate.

Polynucleated cells contain multiple nuclei. Most Acantharean species of protozoa and some fungi in mycorrhizae have naturally polynucleated cells. In humans, skeletal muscle cells, called myocytes, become polynucleated during development; the resulting arrangement of nuclei near the periphery of the cells allows maximal intracellular space for myofibrils. Multinucleated cells can also be abnormal in humans; for example, cells arising from the fusion of monocytes and macrophages, known as giant multinucleated cells, sometimes accompany inflammation and are also implicated in tumor formation.

Evolution

As the major defining characteristic of the eukaryotic cell, the nucleus' evolutionary origin has been the subject of much speculation. Four major theories have been proposed to explain the existence of the nucleus, although none have yet earned widespread support.

The theory known as the "syntrophic model" proposes that a symbiotic relationship between the archaea and bacteria created the nucleus-containing eukaryotic cell. It is hypothesized that the symbiosis originated when ancient archaea, similar to modern methanogenic archaea, invaded and lived within bacteria similar to modern myxobacteria, eventually forming the early nucleus. This theory is analogous to the accepted theory for the origin of eukaryotic mitochondria and chloroplasts, which are thought to have developed from a similar endosymbiotic relationship between proto-eukaryotes and aerobic bacteria. The archaeal origin of the nucleus is supported by observations that archaea and eukarya have similar genes for certain proteins, including histones. Observations that myxobacteria are motile, can form multicellular complexes, and possess kinases and G proteins similar to eukarya, support a bacterial origin for the eukaryotic cell.

A second model proposes that proto-eukaryotic cells evolved from bacteria without an endosymbiotic stage. This model is based on the existence of modern planctomycetes bacteria that possess a nuclear structure with primitive pores and other compartmentalized membrane structures. A similar proposal states that a eukaryote-like cell, the chronocyte, evolved first and phagocytosed archaea and bacteria to generate the nucleus and the eukaryotic cell.

The most controversial model, known as viral eukaryogenesis, posits that the membrane-bound nucleus, along with other eukaryotic features, originated from the infection of a prokaryote by a virus. The suggestion is based on similarities between eukaryotes and viruses such as linear DNA strands, mRNA capping, and tight binding to proteins (analogizing histones to viral envelopes). One version of the proposal suggests that the nucleus evolved in concert with phagocytosis to form an early cellular "predator". Another variant proposes that eukaryotes originated from early archaea infected by poxviruses, on the basis of observed similarity between the DNA polymerases in modern poxviruses and eukaryotes. It has been suggested that the unresolved question of the evolution of sex could be related to the viral eukaryogenesis hypothesis.

Finally, a very recent proposal suggests that traditional variants of the endosymbiont theory are insufficiently powerful to explain the origin of the eukaryotic nucleus. This model, termed the exomembrane hypothesis, suggests that the nucleus instead originated from a single ancestral cell that evolved a second exterior cell membrane; the interior membrane enclosing the original cell then became the nuclear membrane and evolved increasingly elaborate pore structures for passage of internally synthesized cellular components such as ribosomal subunits.

References

1. Harris, H (1999). The Birth of the Cell. New Haven: Yale University Press.
2. Brown, Robert (1866). "On the Organs and Mode of Fecundation of Orchidex and Asclepiadea". Miscellaneous Botanical Works. I: 511–514.
3. ^ Cremer, Thomas (1985). Von der Zellenlehre zur Chromosomentheorie. Berlin, Heidelberg, New York, Tokyo: Springer Verlag. ISBN 3-540-13987-7. Online Version here
4. ^ Lodish, H (2004). Molecular Cell Biology (5th ed.). New York: WH Freeman. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
5. ^ Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter, ed. (2002). Molecular Biology of the Cell (4th ed.). Garland Science.{{cite book}}: CS1 maint: multiple names: editors list (link)
6. Paine P, Moore L, Horowitz S (1975). "Nuclear envelope permeability". Nature. 254 (5496): 109–114. PMID 1117994.{{cite journal}}: CS1 maint: multiple names: authors list (link)
7. Rodney Rhoades, Richard Pflanzer, ed. (1996). "Ch3". Human Physiology (3rd ed.). Saunders College Publishing.
8. Shulga N, Mosammaparast N, Wozniak R, Goldfarb D (2000). "Yeast nucleoporins involved in passive nuclear envelope permeability". J Cell Biol. 149 (5): 1027–1038. PMID 10831607.{{cite journal}}: CS1 maint: multiple names: authors list (link)
9. ^ Pemberton L, Paschal B (2005). "Mechanisms of receptor-mediated nuclear import and nuclear export". Traffic. 6 (3): 187–198. PMID 15702987.
10. Stuurman N, Heins S, Aebi U (1998). "Nuclear lamins: their structure, assembly, and interactions". J Struct Biol. 122 (1–2): 42–66. PMID 9724605.{{cite journal}}: CS1 maint: multiple names: authors list (link)
11. Goldman A, Moir R, Montag-Lowy M, Stewart M, Goldman R (1992). "Pathway of incorporation of microinjected lamin A into the nuclear envelope". J Cell Biol. 119 (4): 725–735. PMID 1429833.{{cite journal}}: CS1 maint: multiple names: authors list (link)
12. ^ Goldman R, Gruenbaum Y, Moir R, Shumaker D, Spann T (2002). "Nuclear lamins: building blocks of nuclear architecture". Genes Dev. 16 (5): 533–547. PMID 11877373.{{cite journal}}: CS1 maint: multiple names: authors list (link)
13. Moir RD, Yoona M, Khuona S, Goldman RD. (2000). "Nuclear Lamins A and B1: Different Pathways of Assembly during Nuclear Envelope Formation in Living Cells". Journal of Cell Biology. 151 (6): 1155–1168. PMID 11121432.{{cite journal}}: CS1 maint: multiple names: authors list (link)
14. "Alteration of nuclear lamin organization inhibits RNA polymerase II–dependent transcription". Journal of Cell Biology. 156 (4): 603–608. 2002. PMID 11854306. {{cite journal}}: Unknown parameter |authors= ignored (help)
15. Mounkes LC, Stewart CL (2004). "Aging and nuclear organization: lamins and progeria". Current Opinion in Cell Biology. 16: 322–327. PMID 15145358.
16. Ehrenhofer-Murray A (2004). "Chromatin dynamics at DNA replication, transcription and repair". Eur J Biochem. 271 (12): 2335–2349. PMID 15182349.
17. Grigoryev S, Bulynko Y, Popova E (2006). "The end adjusts the means: heterochromatin remodelling during terminal cell differentiation". Chromosome Res. 14 (1): 53–69. PMID 16506096.{{cite journal}}: CS1 maint: multiple names: authors list (link)
18. Schardin, Margit (Dec 1985). "Specific staining of human chromosomes in Chinese hamster x man hybrid cell lines demonstrates interphase chromosome territories". Human Genetics. 71 (4). Springer Berlin / Heidelberg: 281–287. doi:10.1007/BF00388452. PMID 2416668. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
19. Lamond, Angus I. (24 April 1998). "Structure and Function in the Nucleus". Science. 280: 547–553. PMID 9554838. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
20. Kurz, A (1996). "Active and inactive genes localize preferentially in the periphery of chromosome territories". The Journal of Cell Biology. 135. The Rockefeller University Press: 1195–1205. PMID 8947544. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
21. NF Rothfield, BD Stollar (1967). "The Relation of Immunoglobulin Class, Pattern of Antinuclear Antibody, and Complement-Fixing Antibodies to DNA in Sera from Patients with Systemic Lupus Erythematosus". J Clin Invest. 46 (11): 1785–1794. PMID 4168731.
22. S Barned, AD Goodman, DH Mattson (1995). "Frequency of anti-nuclear antibodies in multiple sclerosis". Neurology. 45 (2): 384–385. PMID 7854544.{{cite journal}}: CS1 maint: multiple names: authors list (link)
23. Hernandez-Verdun, Daniele (2006). "Nucleolus: from structure to dynamics". Histochem. Cell. Biol (125): 127–137. doi:10.1007/s00418-005-0046-4.
24. ^ Lamond, Angus I. "Nuclear substructure and dynamics". Current Biology. 13 (21): R825–828. PMID 14588256. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
25. ^ Cioce M, Lamond A. "Cajal bodies: a long history of discovery". Annu Rev Cell Dev Biol. 21: 105–131. PMID 16212489.
26. ^ Pollard, Thomas D. (2004). Cell Biology. Philadelphia: Saunders. ISBN 0-7216-3360-9. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
27. ^ Dundr, Miroslav (2001). "Functional architecture in the cell nucleus". Biochem. J. (356): 297–310. PMID 11368755. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
28. Fox, Archa (2007-03-07). "Paraspeckle Size" (Interview). Interviewed by R. Sundby. {{cite interview}}: Unknown parameter |city= ignored (|location= suggested) (help)
29. Goebel, H.H. (1997). "Nemaline myopathy with intranuclear rods—intranuclear rod myopathy". Neuromuscular Disorders. 7 (1): 13–19. PMID 9132135. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
30. ^ Matera AG, Frey MA. (1998). "Coiled Bodies and Gems: Janus or Gemini?". American Journal of Human Genetics. 63 (2): 317–321. PMID 9683623.
31. Matera, A. Gregory (1998). "Of Coiled Bodies, Gems, and Salmon". Journal of Cellular Biochemistry (70): 181–192. PMID 9671224.
32. Saunders WS, Cooke CA, Earnshaw WC (1991). "Compartmentalization within the nucleus: discovery of a novel subnuclear region". Journal of Cellular Biology. 115 (4): 919–931.{{cite journal}}: CS1 maint: multiple names: authors list (link) PMID 1955462
33. Pombo A, Cuello P, Schul W, Yoon J, Roeder R, Cook P, Murphy S (1998). "Regional and temporal specialization in the nucleus: a transcriptionally active nuclear domain rich in PTF, Oct1 and PIKA antigens associates with specific chromosomes early in the cell cycle". EMBO J. 17 (6): 1768–1778. PMID 9501098.{{cite journal}}: CS1 maint: multiple names: authors list (link)
34. ^ Fox, Archa; et al. (2002). "Paraspeckles:A Novel Nuclear Domain". Current Biology. 12: 13–25. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |quotes= ignored (help)
35. ^ Fox, Archa (2004). "Nuclear Compartments: Paraspeckles". Nuclear Protein Database. Retrieved 2007-03-06. {{cite web}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
36. ^ Fox, A.; et al. (2005). "P54nrb Forms a Heterodimer with PSP1 That Localizes to Paraspeckles in an RNA-dependent Manner". Molecular Biology of the Cell. 16: 5304–5315. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |quotes= ignored (help) PMID 16148043
37. Handwerger, Korie E. (2006). "Subnuclear organelles: new insights into form and function". TRENDS in Cell Biology. 16 (1): 19–26. doi:10.1016/j.tcb.2005.11.005. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
38. Lehninger, Albert L. (2000). Lehninger principles of biochemistry (3rd ed.). New York: Worth Publishers. ISBN 1-57259-931-6. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
39. Moreno F, Ahuatzi D, Riera A, Palomino CA, Herrero P. (2005). "Glucose sensing through the Hxk2-dependent signalling pathway". Biochem Soc Trans. 33 (1): 265–268.{{cite journal}}: CS1 maint: multiple names: authors list (link) PMID 15667322
40. Görlich, Dirk (1999). "Transport between the cell nucleus and the cytoplasm". Ann. Rev. Cell Dev. Biol. (15): 607–660. PMID 10611974. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
41. Watson, JD (2004). "Ch9–10". Molecular Biology of the Gene (5th ed. ed.). Peason Benjamin Cummings; CSHL Press. {{cite book}}: |edition= has extra text (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
42. Lippincott-Schwartz, Jennifer (7 March 2002). "Cell biology: Ripping up the nuclear envelope". Nature. 416 (6876): 31–32. doi:10.1038/416031a.
43. ^ Boulikas T (1995). "Phosphorylation of transcription factors and control of the cell cycle". Crit Rev Eukaryot Gene Expr. 5 (1): 1–77. PMID 7549180.
44. Steen R, Collas P (2001). "Mistargeting of B-type lamins at the end of mitosis: implications on cell survival and regulation of lamins A/C expression". J Cell Biol. 153 (3): 621–626. PMID 11331311.
45. Skutelsky, E. (June 1970). "Comparative study of nuclear expulsion from the late erythroblast and cytokinesis". J Cell Biol (60(3)): 625–635. PMID 5422968. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
46. Torous, DK (2000). "Enumeration of micronucleated reticulocytes in rat peripheral blood: a flow cytometric study". Mutat Res (465(1–2)): 91–99. PMID 10708974. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
47. Hutter, KJ (1982). "Rapid detection of mutagen induced micronucleated erythrocytes by flow cytometry". Histochemistry (75(3)): 353–362. PMID 7141888. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
48. Zettler, LA (1997). "Phylogenetic relationships between the Acantharea and the Polycystinea: A molecular perspective on Haeckel's Radiolaria". Proc Natl Acad Sci USA (94): 11411–11416. PMID 9326623. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
49. Horton, TR (2006). "The number of nuclei in basidiospores of 63 species of ectomycorrhizal Homobasidiomycetes". Mycologia (98(2)): 233–238. PMID 16894968. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help)
50. McInnes, A (1988). "Interleukin 4 induces cultured monocytes/macrophages to form giant multinucleated cells". J Exp Med (167): 598–611. PMID 3258008. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
51. Goldring, SR (1987). "Human giant cell tumors of bone identification and characterization of cell types". J Clin Invest (79(2)): 483–491. PMID 3027126. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
52. Pennisi E. (2004). "Evolutionary biology. The birth of the nucleus". Science. 305 (5685): 766–768. PMID 15297641.
53. Margulis, Lynn (1981). Symbiosis in Cell Evolution. San Francisco: W. H. Freeman and Company. pp. 206–227. ISBN 0-7167-1256-3.
54. Lopez-Garcia P, Moreira D. (2006). "Selective forces for the origin of the eukaryotic nucleus". Bioessays. 28 (5): 525–533. PMID 16615090.
55. Fuerst JA. (2005). "Intracellular compartmentation in planctomycetes". Annu Rev Microbiol. 59: 299–328. PMID 15910279.
56. Hartman H, Fedorov A. (2002). "The origin of the eukaryotic cell: a genomic investigation". Proc Natl Acad Sci U S A. 99 (3): 1420–1425. PMID 11805300.
57. Bell PJ. (2001). "Viral eukaryogenesis: was the ancestor of the nucleus a complex DNA virus?" J Mol Biol Sep;53(3):251–256. PMID 11523012
58. Takemura M. (2001). Poxviruses and the origin of the eukaryotic nucleus. J Mol Evol 52(5):419–425. PMID 11443345
59. Villarreal L, DeFilippis V (2000). "A hypothesis for DNA viruses as the origin of eukaryotic replication proteins". J Virol. 74 (15): 7079–7084. PMID 10888648.
60. Bell PJ. (2006). "Sex and the eukaryotic cell cycle is consistent with a viral ancestry for the eukaryotic nucleus." J Theor Biol 2006 Nov 7;243(1):54–63. PMID 16846615
61. de Roos AD (2006). "The origin of the eukaryotic cell based on conservation of existing interfaces". Artif Life. 12 (4): 513–523. PMID 16953783.

Further reading

• Goldman, Robert D. (2002). "Nuclear lamins: building blocks of nuclear architecture". Genes & Dev. (16): 533–547. doi:10.1101/gad.960502. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

A review article about nuclear lamins, explaining their structure and various roles

• Görlich, Dirk (1999). "Transport between the cell nucleus and the cytoplasm". Ann. Rev. Cell Dev. Biol. (15): 607–660. PMID 10611974. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

A review article about nuclear transport, explains the principles of the mechanism, and the various transport pathways

• Lamond, Angus I. (24 APRIL 1998). "Structure and Function in the Nucleus". Science. 280: 547–553. PMID 9554838. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

A review article about the nucleus, explaining the structure of chromosomes within the organelle, and describing the nucleolus and other subnuclear bodies

• Pennisi E. (2004). "Evolutionary biology. The birth of the nucleus". Science. 305 (5685): 766–768. PMID 15297641.

A review article about the evolution of the nucleus, explaining a number of different theories

• Pollard, Thomas D. (2004). Cell Biology. Philadelphia: Saunders. ISBN 0-7216-3360-9. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

A university level textbook focusing on cell biology. Contains information on nucleus structure and function, including nuclear transport, and subnuclear domains

External links

• cellnucleus.com Website covering structure and function of the nucleus from the Department of Oncology at the University of Alberta.
• The Nuclear Protein Database Information on nuclear components.
• The Nucleus Collection in the Image & Video Library of The American Society for Cell Biology contains peer-reviewed still images and video clips that illustrate the nucleus.
• Nuclear Envelope and Nuclear Import Section from Landmark Papers in Cell Biology, Joseph G. Gall, J. Richard McIntosh, eds., contains digitized commentaries and links to seminal research papers on the nucleus. Published online in the Image & Video Library of The American Society for Cell Biology
• Cytoplasmic patterns generated by human antibodies

Gallery of nucleus images

• Organelles