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NucleusCell

Cell nucleus 1

Cell nucleus

HeLa cells stained for DNA with the Blue Hoechst dye. The central and rightmost cell arein interphase, thus their entire nuclei are labeled. On the left a cell is going through

mitosis and its DNA has condensed ready for division.

Schematic of typical animal cell, showing subcellular components. Organelles: (1)nucleolus (2) nucleus (3) ribosome (4) vesicle (5) rough endoplasmic reticulum (ER) (6)

Golgi apparatus (7) Cytoskeleton (8) smooth ER (9) mitochondria (10) vacuole (11)cytoplasm (12) lysosome (13) centrioles

In cell biology, the nucleus (pl. nuclei;from Latin nucleus or nuculeus,meaning kernel), also sometimesreferred to as the "control center", is amembrane-enclosed organelle found ineukaryotic cells. It contains most of thecell's genetic material, organized asmultiple long linear DNA molecules incomplex with a large variety ofproteins, such as histones, to formchromosomes. The genes within thesechromosomes are the cell's nucleargenome. The function of the nucleus isto maintain the integrity of these genesand to control the activities of the cellby regulating gene expression — thenucleus is therefore the control centerof the cell.

The main structures making up thenucleus are the nuclear envelope, adouble membrane that encloses theentire organelle and separates itscontents from the cellular cytoplasm,and the nuclear lamina, a meshworkwithin the nucleus that addsmechanical support, much like thecytoskeleton supports the cell as awhole. Because the nuclear membraneis impermeable to most molecules,nuclear pores are required to allowmovement of molecules across theenvelope. These pores cross both of themembranes, providing a channel thatallows free movement of smallmolecules and ions. The movement oflarger molecules such as proteins iscarefully controlled, and requires active transport regulated by carrier proteins. Nuclear transport is crucial to cellfunction, as movement through the pores is required for both gene expression and chromosomal maintenance.

Cell nucleus 2

Entry of material into the nucleus through phagocytosis. The phagosome travels from thecell membrane to the nucleus, and then is engulfed by the nucleus, releasing its contents.

Although the interior of the nucleusdoes not contain any membrane-boundsubcompartments, its contents are notuniform, and a number of subnuclearbodies exist, made up of uniqueproteins, RNA molecules, andparticular parts of the chromosomes.The best known of these is thenucleolus, which is mainly involved inthe assembly of ribosomes. After beingproduced in the nucleolus, ribosomesare exported to the cytoplasm wherethey translate mRNA.

History

Oldest known depiction of cells and their nuclei by Antonie vanLeeuwenhoek, 1719.

Drawing of a Chironomus salivary gland cellpublished by Walther Flemming in 1882. The

nucleus contains Polytene chromosomes.

The nucleus was the first organelle to bediscovered. The probably oldest preserved drawingdates back to the early microscopist Antonie vanLeeuwenhoek (1632 – 1723). He observed a"Lumen", the nucleus, in the red blood cells ofsalmon[1] . Unlike mammalian red blood cells,those of other vertebrates still possess nuclei. Thenucleus was also described by Franz Bauer in1804[2] and in more detail in 1831 by Scottishbotanist Robert Brown in a talk at the LinneanSociety of London. Brown was studying orchidsmicroscopically when he observed an opaque area,which he called the areola or nucleus, in the cellsof the flower's outer layer.[3] He did not suggest apotential function. In 1838 Matthias Schleidenproposed that the nucleus plays a role in generatingcells, thus he introduced the name "Cytoblast" (cellbuilder). He believed that he had observed newcells assembling around "cytoblasts". Franz Meyenwas a strong opponent of this view having alreadydescribed cells multiplying by division andbelieving that many cells would have no nuclei.The idea that cells can be generated de novo, bythe "cytoblast" or otherwise, contradicted work byRobert Remak (1852) and Rudolf Virchow (1855)

who decisively propagated the new paradigm that cells are generated solely by cells ("Omnis cellula e cellula"). Thefunction of the nucleus remained unclear.[4]

Cell nucleus 3

Between 1876 and 1878 Oscar Hertwig published several studies on the fertilization of sea urchin eggs, showing thatthe nucleus of the sperm enters the oocyte and fuses with its nucleus. This was the first time it was suggested that anindividual develops from a (single) nucleated cell. This was in contradiction to Ernst Haeckel's theory that thecomplete phylogeny of a species would be repeated during embryonic development, including generation of the firstnucleated cell from a "Monerula", a structureless mass of primordial mucus ("Urschleim"). Therefore, the necessityof the sperm nucleus for fertilization was discussed for quite some time. However, Hertwig confirmed hisobservation in other animal groups, e.g. amphibians and molluscs. Eduard Strasburger produced the same results forplants (1884). This paved the way to assign the nucleus an important role in heredity. In 1873 August Weismannpostulated the equivalence of the maternal and paternal germ cells for heredity. The function of the nucleus as carrierof genetic information became clear only later, after mitosis was discovered and the Mendelian rules wererediscovered at the beginning of the 20th century; the chromosome theory of heredity was developed.[4]

StructuresThe nucleus is the largest cellular organelle in animals.[5] In mammalian cells, the average diameter of the nucleus isapproximately 6 micrometers (μm), which occupies about 10% of the total cell volume.[6] The viscous liquid withinit is called nucleoplasm, and is similar in composition to the cytosol found outside the nucleus.[7] It appears as adense, roughly spherical organelle.

Nuclear envelope and pores

The eukaryotic cell nucleus. Visible in this diagram are theribosome-studded double membranes of the nuclear envelope, theDNA (complexed as chromatin), and the nucleolus. Within the cell

nucleus is a viscous liquid called nucleoplasm, similar to thecytoplasm found outside the nucleus.

A cross section of a nuclear pore on the surface of the nuclearenvelope (1). Other diagram labels show (2) the outer ring, (3)

spokes, (4) basket, and (5) filaments.

The nuclear envelope otherwise known as nuclear membrane consists of two cellular membranes, an inner and anouter membrane, arranged parallel to one another and separated by 10 to 50 nanometers (nm). The nuclear envelopecompletely encloses the nucleus and separates the cell's genetic material from the surrounding cytoplasm, serving asa barrier to prevent macromolecules from diffusing freely between the nucleoplasm and the cytoplasm.[8] The outernuclear membrane is continuous with the membrane of the rough endoplasmic reticulum (RER), and is similarlystudded with ribosomes. The space between the membranes is called the perinuclear space and is continuous with theRER lumen.

Cell nucleus 4

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 ofaround 50 (in yeast) to 100 proteins (in vertebrates).[5] The pores are 100 nm in total diameter; however, the gapthrough which molecules freely diffuse is only about 9 nm wide, due to the presence of regulatory systems within thecenter of the pore. This size allows the free passage of small water-soluble molecules while preventing largermolecules, such as nucleic acids and larger proteins, from inappropriately entering or exiting the nucleus. Theselarge molecules must be actively transported into the nucleus instead. The nucleus of a typical mammalian cell willhave about 3000 to 4000 pores throughout its envelope,[9] each of which contains a donut-shaped,eightfold-symmetric ring-shaped structure at a position where the inner and outer membranes fuse.[10] Attached tothe ring is a structure called the nuclear basket that extends into the nucleoplasm, and a series of filamentousextensions that reach into the cytoplasm. Both structures serve to mediate binding to nuclear transport proteins.[5]

Most proteins, ribosomal subunits, and some RNAs are transported through the pore complexes in a processmediated by a family of transport factors known as karyopherins. Those karyopherins that mediate movement intothe 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.[11] Steroid hormones suchas cortisol and aldosterone, as well as other small lipid-soluble molecules involved in intercellular signaling candiffuse through the cell membrane and into the cytoplasm, where they bind nuclear receptor proteins that aretrafficked into the nucleus. There they serve as transcription factors when bound to their ligand; in the absence ofligand many such receptors function as histone deacetylases that repress gene expression.[5]

Nuclear laminaIn animal cells, two networks of intermediate filaments provide the nucleus with mechanical support: the nuclearlamina forms an organized meshwork on the internal face of the envelope, while less organized support is providedon the cytosolic face of the envelope. Both systems provide structural support for the nuclear envelope andanchoring sites for chromosomes and nuclear pores.[6]

The nuclear lamina is mostly composed of lamin proteins. Like all proteins, lamins are synthesized in the cytoplasmand later transported into the nucleus interior, where they are assembled before being incorporated into the existingnetwork of nuclear lamina.[12] [13] Lamins are also found inside the nucleoplasm where they form another regularstructure, known as the nucleoplasmic veil,[14] that is visible using fluorescence microscopy. The actual function ofthe veil is not clear, although it is excluded from the nucleolus and is present during interphase.[15] The laminstructures that make up the veil bind chromatin and disrupting their structure inhibits transcription of protein-codinggenes.[16]

Like the components of other intermediate filaments, the lamin monomer contains an alpha-helical domain used bytwo monomers to coil around each other, forming a dimer structure called a coiled coil. Two of these dimerstructures then join side by side, in an antiparallel arrangement, to form a tetramer called a protofilament. Eight ofthese protofilaments form a lateral arrangement that is twisted to form a ropelike filament. These filaments can beassembled or disassembled in a dynamic manner, meaning that changes in the length of the filament depend on thecompeting rates of filament addition and removal.[6]

Mutations in lamin genes leading to defects in filament assembly are known as laminopathies. The most notablelaminopathy is the family of diseases known as progeria, which causes the appearance of premature aging in itssufferers. The exact mechanism by which the associated biochemical changes give rise to the aged phenotype is notwell understood.[17]

Cell nucleus 5

Chromosomes

A mouse fibroblast nucleus in which DNA is stainedblue. The distinct chromosome territories of

chromosome 2 (red) and chromosome 9 (green) arevisible stained with fluorescent in situ hybridization.

The cell nucleus contains the majority of the cell's geneticmaterial, in the form of multiple linear DNA molecules organizedinto structures called chromosomes. During most of the cell cyclethese are organized in a DNA-protein complex known aschromatin, and during cell division the chromatin can be seen toform the well defined chromosomes familiar from a karyotype. Asmall fraction of the cell's genes are located instead in themitochondria.

There are two types of chromatin. Euchromatin is the less compactDNA form, and contains genes that are frequently expressed bythe cell.[18] The other type, heterochromatin, is the more compactform, and contains DNA that are infrequently transcribed. Thisstructure is further categorized into facultative heterochromatin,consisting of genes that are organized as heterochromatin only incertain cell types or at certain stages of development, andconstitutive heterochromatin that consists of chromosomestructural components such as telomeres and centromeres.[19]

During interphase the chromatin organizes itself into discrete individual patches,[20] called chromosometerritories.[21] Active genes, which are generally found in the euchromatic region of the chromosome, tend to belocated towards the chromosome's territory boundary.[22]

Antibodies to certain types of chromatin organization, particularly nucleosomes, have been associated with a numberof autoimmune diseases, such as systemic lupus erythematosus.[23] These are known as anti-nuclear antibodies(ANA) and have also been observed in concert with multiple sclerosis as part of general immune systemdysfunction.[24] As in the case of progeria, the role played by the antibodies in inducing the symptoms ofautoimmune diseases is not obvious.

Nucleolus

An electron micrograph of a cell nucleus, showing thedarkly stained nucleolus.

The nucleolus is a discrete densely stained structure found in thenucleus. It is not surrounded by a membrane, and is sometimescalled a suborganelle. It forms around tandem repeats of rDNA,DNA coding for ribosomal RNA (rRNA). These regions are callednucleolar organizer regions (NOR). The main roles of thenucleolus are to synthesize rRNA and assemble ribosomes. Thestructural cohesion of the nucleolus depends on its activity, asribosomal assembly in the nucleolus results in the transientassociation of nucleolar components, facilitating further ribosomalassembly, and hence further association. This model is supportedby observations that inactivation of rDNA results in interminglingof nucleolar structures.[25]

The first step in ribosomal assembly is transcription of the rDNA,by a protein called RNA polymerase I, forming a large pre-rRNAprecursor. This is cleaved into the subunits 5.8S, 18S, and 28S

Cell nucleus 6

rRNA.[26] The transcription, post-transcriptional processing, and assembly of rRNA occurs in the nucleolus, aidedby small nucleolar RNA (snoRNA) molecules, some of which are derived from spliced introns from messengerRNAs encoding genes related to ribosomal function. The assembled ribosomal subunits are the largest structurespassed through the nuclear pores.[5]

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 borderedby 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 andmodification of rRNAs occurs in the DFC, while the latter steps involving protein assembly onto the ribosomalsubunits occurs in the GC.[21]

Other subnuclear bodies

Structure name Structure diameter

Cajal bodies 0.2–2.0 µm[27]

PIKA 5 µm[28]

PML bodies 0.2–1.0 µm[29]

Paraspeckles 0.2–1.0 µm[30]

Speckles 20–25 nm[28]

|+ Subnuclear structure sizes Besides the nucleolus, the nucleus contains a number of other non-membranedelineated bodies. These include Cajal bodies, Gemini of coiled bodies, polymorphic interphase karyosomalassociation (PIKA), promyelocytic leukaemia (PML) bodies, paraspeckles and splicing speckles. Although little isknown about a number of these domains, they are significant in that they show that the nucleoplasm is not uniformmixture, but rather contains organized functional subdomains.[29]

Other subnuclear structures appear as part of abnormal disease processes. For example, the presence of smallintranuclear rods have been reported in some cases of nemaline myopathy. This condition typically results frommutations in actin, and the rods themselves consist of mutant actin as well as other cytoskeletal proteins.[31]

Cajal bodies and gems

A nucleus typically contains between 1 and 10 compact structures called Cajal bodies or coiled bodies (CB), whosediameter measures between 0.2 µm and 2.0 µm depending on the cell type and species.[27] When seen under anelectron microscope, they resemble balls of tangled thread[28] and are dense foci of distribution for the proteincoilin.[32] CBs are involved in a number of different roles relating to RNA processing, specifically small nucleolarRNA (snoRNA) and small nuclear RNA (snRNA) maturation, and histone mRNA modification.[27]

Similar to Cajal bodies are Gemini of coiled bodies, or gems, whose name is derived from the Gemini constellationin reference to their close "twin" relationship with CBs. Gems are similar in size and shape to CBs, and in fact arevirtually indistinguishable under the microscope.[32] Unlike CBs, gems do not contain small nuclearribonucleoproteins (snRNPs), but do contain a protein called survivor of motor neurons (SMN) whose functionrelates to snRNP biogenesis. Gems are believed to assist CBs in snRNP biogenesis,[33] though it has also beensuggested from microscopy evidence that CBs and gems are different manifestations of the same structure.[32]

Cell nucleus 7

PIKA and PTF domains

PIKA domains, or polymorphic interphase karyosomal associations, were first described in microscopy studies in1991. Their function was and remains unclear, though they were not thought to be associated with active DNAreplication, transcription, or RNA processing.[34] They have been found to often associate with discrete domainsdefined by dense localization of the transcription factor PTF, which promotes transcription of snRNA.[35]

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 bodiesand cleavage bodies. It has been suggested that they play a role in regulating transcription.[29]

Paraspeckles

Discovered by Fox et al. in 2002, paraspeckles are irregularly shaped compartments in the nucleus' interchromatinspace.[36] First documented in HeLa cells, where there are generally 10–30 per nucleus,[37] paraspeckles are nowknown to also exist in all human primary cells, transformed cell lines and tissue sections.[38] Their name is derivedfrom their distribution in the nucleus; the "para" is short for parallel and the "speckles" refers to the splicing specklesto which they are always in close proximity.[37]

Paraspeckles are dynamic structures that are altered in response to changes in cellular metabolic activity. They aretranscription dependent[36] and in the absence of RNA Pol II transcription, the paraspeckle disappears and all of itsassociated protein components (PSP1, p54nrb, PSP2, CFI(m)68 and PSF) form a crescent shaped perinucleolar capin the nucleolus. This phenomenon is demonstrated during the cell cycle. In the cell cycle, paraspeckles are presentduring interphase and during all of mitosis except for telophase. During telophase, when the two daughter nuclei areformed, there is no RNA Pol II transcription so the protein components instead form a perinucleolar cap.[38]

Splicing speckles

Sometimes referred to as interchromatin granule clusters or as splicing-factor compartments, speckles are rich insplicing snRNPs and other splicing proteins necessary for pre-mRNA processing.[39] Because of a cell's changingrequirements, the composition and location of these bodies changes according to mRNA transcription and regulationvia phosphorylation of specific proteins.[40]

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

Cell compartmentalizationThe nuclear envelope allows the nucleus to control its contents, and separate them from the rest of the cytoplasmwhere necessary. This is important for controlling processes on either side of the nuclear membrane. In some caseswhere a cytoplasmic process needs to be restricted, a key participant is removed to the nucleus, where it interactswith transcription factors to downregulate the production of certain enzymes in the pathway. This regulatorymechanism 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 proteinremoves hexokinase to the nucleus,[41] where it forms a transcriptional repressor complex with nuclear proteins toreduce the expression of genes involved in glycolysis.[42]

Cell nucleus 8

In order to control which genes are being transcribed, the cell separates some transcription factor proteinsresponsible for regulating gene expression from physical access to the DNA until they are activated by othersignaling pathways. This prevents even low levels of inappropriate gene expression. For example in the case ofNF-κB-controlled genes, which are involved in most inflammatory responses, transcription is induced in response toa signal pathway such as that initiated by the signaling molecule TNF-α, binds to a cell membrane receptor, resultingin the recruitment of signalling proteins, and eventually activating the transcription factor NF-κB. A nuclearlocalisation 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.[6]

The compartmentalization allows the cell to prevent translation of unspliced mRNA.[43] Eukaryotic mRNA containsintrons that must be removed before being translated to produce functional proteins. The splicing is done inside thenucleus before the mRNA can be accessed by ribosomes for translation. Without the nucleus ribosomes wouldtranslate newly transcribed (unprocessed) mRNA resulting in misformed and nonfunctional proteins.

Gene expression

A micrograph of ongoing gene transcription ofribosomal RNA illustrating the growing primary

transcripts. "Begin" indicates the 3' end of the DNA,where new RNA synthesis begins; "end" indicates the

5' end, where the primary transcripts are almostcomplete.

Gene expression first involves transcription, in which DNA is usedas a template to produce RNA. In the case of genes encodingproteins, that RNA produced from this process is messenger RNA(mRNA), which then needs to be translated by ribosomes to forma protein. As ribosomes are located outside the nucleus, mRNAproduced needs to be exported.[44]

Since the nucleus is the site of transcription, it also contains avariety of proteins which either directly mediate transcription orare involved in regulating the process. These proteins includehelicases that unwind the double-stranded DNA molecule tofacilitate access to it, RNA polymerases that synthesize thegrowing RNA molecule, topoisomerases that change the amountof supercoiling in DNA, helping it wind and unwind, as well as alarge variety of transcription factors that regulate expression.[45]

Processing of pre-mRNA

Newly synthesized mRNA molecules are known as primarytranscripts or pre-mRNA. They must undergo post-transcriptionalmodification in the nucleus before being exported to thecytoplasm; 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 incomplexes known as heterogeneous ribonucleoprotein particles (hnRNPs). Addition of the 5' cap occursco-transcriptionally and is the first step in post-transcriptional modification. The 3' poly-adenine tail is only addedafter transcription is complete.

RNA splicing, carried out by a complex called the spliceosome, is the process by which introns, or regions of DNAthat do not code for protein, are removed from the pre-mRNA and the remaining exons connected to re-form a singlecontinuous molecule. This process normally occurs after 5' capping and 3' polyadenylation but can begin beforesynthesis is complete in transcripts with many exons.[5] 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

Cell nucleus 9

of DNA.

Dynamics and regulation

Nuclear transport

Macromolecules, such as RNA and proteins, are actively transported across the nuclearmembrane in a process called the Ran-GTP nuclear transport cycle.

The entry and exit of large moleculesfrom the nucleus is tightly controlledby the nuclear pore complexes.Although small molecules can enterthe nucleus without regulation,[46]

macromolecules such as RNA andproteins require associationkaryopherins called importins to enterthe nucleus and exportins to exit."Cargo" proteins that must betranslocated from the cytoplasm to thenucleus contain short amino acidsequences known as nuclearlocalization signals which are boundby importins, while those transportedfrom the nucleus to the cytoplasmcarry nuclear export signals bound byexportins. The ability of importins and exportins to transport their cargo is regulated by GTPases, enzymes thathydrolyze the molecule guanosine triphosphate to release energy. The key GTPase in nuclear transport is Ran, whichcan bind either GTP or GDP (guanosine diphosphate) depending on whether it is located in the nucleus or thecytoplasm. Whereas importins depend on RanGTP to dissociate from their cargo, exportins require RanGTP in orderto bind to their cargo.[11]

Nuclear import depends on the importin binding its cargo in the cytoplasm and carrying it through the nuclear poreinto the nucleus. Inside the nucleus, RanGTP acts to separate the cargo from the importin, allowing the importin toexit the nucleus and be reused. Nuclear export is similar, as the exportin binds the cargo inside the nucleus in aprocess 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 afterpost-transcriptional modification is complete. This quality-control mechanism is important due to the thesemolecules' central role in protein translation; mis-expression of a protein due to incomplete excision of exons ormis-incorporation of amino acids could have negative consequences for the cell; thus incompletely modified RNAthat reaches the cytoplasm is degraded rather than used in translation.[5]

Cell nucleus 10

Assembly and disassembly

An image of a newt lung cell stained with fluorescent dyesduring metaphase. The mitotic spindle can be seen, stained

green, attached to the two sets of chromosomes, stained lightblue. All chromosomes but one are already at the metaphase

plate.

During its lifetime a nucleus may be broken down, either inthe process of cell division or as a consequence ofapoptosis, a regulated form of cell death. During theseevents, the structural components of the nucleus—theenvelope and lamina—are systematically degraded.

During the cell cycle the cell divides to form two cells. Inorder for this process to be possible, each of the newdaughter cells must have a full set of genes, a processrequiring replication of the chromosomes as well assegregation of the separate sets. This occurs by thereplicated chromosomes, the sister chromatids, attaching tomicrotubules, which in turn are attached to differentcentrosomes. The sister chromatids can then be pulled toseparate locations in the cell. In many cells the centrosomeis located in the cytoplasm, outside the nucleus, themicrotubules would be unable to attach to the chromatids inthe presence of the nuclear envelope.[47] Therefore the earlystages in the cell cycle, beginning in prophase and until

around prometaphase, the nuclear membrane is dismantled.[14] Likewise, during the same period, the nuclear laminais also disassembled, a process regulated by phosphorylation of the lamins.[48] Towards the end of the cell cycle, thenuclear membrane is reformed, and around the same time, the nuclear lamina are reassembled by dephosphorylatingthe lamins.[48]

However, in dinoflagellates the nuclear envelope remains intact, the centrosomes are located in the cytoplasm, andthe microtubules come in contact with chromosomes, whose centromeric regions are incorporated into the nuclearenvelope (the so-called closed mitosis with extranuclear spindle). In many other protists (e.g. ciliates, sporozoans)and fungi the centrosomes are intranuclear, and their nuclear envelope also does not disassemle during cell division.

Apoptosis is a controlled process in which the cell's structural components are destroyed, resulting in death of thecell. Changes associated with apoptosis directly affect the nucleus and its contents, for example in the condensationof chromatin and the disintegration of the nuclear envelope and lamina. The destruction of the lamin networks iscontrolled by specialized apoptotic proteases called caspases, which cleave the lamin proteins and thus degrade thenucleus' structural integrity. Lamin cleavage is sometimes used as a laboratory indicator of caspase activity in assaysfor early apoptotic activity.[14] Cells that express mutant caspase-resistant lamins are deficient in nuclear changesrelated to apoptosis, suggesting that lamins play a role in initiating the events that lead to apoptotic degradation ofthe nucleus.[14] Inhibition of lamin assembly itself is an inducer of apoptosis.[49]

The nuclear envelope acts as a barrier that prevents both DNA and RNA viruses from entering the nucleus. Someviruses require access to proteins inside the nucleus in order to replicate and/or assemble. DNA viruses, such asherpesvirus replicate and assemble in the cell nucleus, and exit by budding through the inner nuclear membrane. Thisprocess is accompanied by disassembly of the lamina on the nuclear face of the inner membrane.[14]

Cell nucleus 11

Anucleated and polynucleated cells

Human red blood cells, like those of othermammals, lack nuclei. This occurs as anormal part of the cells' development.

Although most cells have a single nucleus, some eukaryotic cell types haveno nucleus, and others have many nuclei. This can be a normal process, as inthe maturation of mammalian red blood cells, or a result of faulty celldivision.

Anucleated cells contain no nucleus and are therefore incapable of dividingto produce daughter cells. The best-known anucleated cell is the mammalianred blood cell, or erythrocyte, which also lacks other organelles such asmitochondria and serves primarily as a transport vessel to ferry oxygen fromthe lungs to the body's tissues. Erythrocytes mature through erythropoiesis inthe bone marrow, where they lose their nuclei, organelles, and ribosomes.The nucleus is expelled during the process of differentiation from anerythroblast to a reticulocyte, which is the immediate precursor of the matureerythrocyte.[50] The presence of mutagens may induce the release of someimmature "micronucleated" erythrocytes into the bloodstream.[51] [52]

Anucleated cells can also arise from flawed cell division in which onedaughter lacks a nucleus and the other has two nuclei.

Polynucleated cells contain multiple nuclei. Most Acantharean species of protozoa[53] and some fungi inmycorrhizae[54] have naturally polynucleated cells. Other examples include the intestinal parasites in the genusGiardia, which have two nuclei per cell.[55] In humans, skeletal muscle cells, called myocytes, becomepolynucleated during development; the resulting arrangement of nuclei near the periphery of the cells allowsmaximal intracellular space for myofibrils.[5] Multinucleated cells can also be abnormal in humans; for example,cells arising from the fusion of monocytes and macrophages, known as giant multinucleated cells, sometimesaccompany inflammation[56] and are also implicated in tumor formation.[57]

EvolutionAs the major defining characteristic of the eukaryotic cell, the nucleus' evolutionary origin has been the subject ofmuch speculation. Four major theories have been proposed to explain the existence of the nucleus, although nonehave yet earned widespread support.[58]

The theory known as the "syntrophic model" proposes that a symbiotic relationship between the archaea and bacteriacreated 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 eukaryoticmitochondria and chloroplasts, which are thought to have developed from a similar endosymbiotic relationshipbetween proto-eukaryotes and aerobic bacteria.[59] The archaeal origin of the nucleus is supported by observationsthat archaea and eukarya have similar genes for certain proteins, including histones. Observations that myxobacteriaare motile, can form multicellular complexes, and possess kinases and G proteins similar to eukarya, support abacterial origin for the eukaryotic cell.[60]

A second model proposes that proto-eukaryotic cells evolved from bacteria without an endosymbiotic stage. Thismodel is based on the existence of modern planctomycetes bacteria that possess a nuclear structure with primitivepores and other compartmentalized membrane structures.[61] A similar proposal states that a eukaryote-like cell, thechronocyte, evolved first and phagocytosed archaea and bacteria to generate the nucleus and the eukaryotic cell.[62]

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

Cell nucleus 12

proteins (analogizing histones to viral envelopes). One version of the proposal suggests that the nucleus evolved inconcert with phagocytosis to form an early cellular "predator".[63] Another variant proposes that eukaryotesoriginated from early archaea infected by poxviruses, on the basis of observed similarity between the DNApolymerases in modern poxviruses and eukaryotes.[64] [65] It has been suggested that the unresolved question of theevolution of sex could be related to the viral eukaryogenesis hypothesis.[66]

Finally, a very recent proposal suggests that traditional variants of the endosymbiont theory are insufficientlypowerful to explain the origin of the eukaryotic nucleus. This model, termed the exomembrane hypothesis, suggeststhat the nucleus instead originated from a single ancestral cell that evolved a second exterior cell membrane; theinterior membrane enclosing the original cell then became the nuclear membrane and evolved increasingly elaboratepore structures for passage of internally synthesized cellular components such as ribosomal subunits.[67]

Further reading• Goldman, Robert D.; Gruenbaum, Y; Moir, RD; Shumaker, DK; Spann, TP (2002). "Nuclear lamins: building

blocks of nuclear architecture". Genes & Dev. 16 (16): 533–547. doi:10.1101/gad.960502. PMID 11877373.A review article about nuclear lamins, explaining their structure and various roles

• Görlich, Dirk; Kutay, U (1999). "Transport between the cell nucleus and the cytoplasm". Ann. Rev. Cell Dev.Biol. 15 (15): 607–660. doi:10.1146/annurev.cellbio.15.1.607. PMID 10611974.

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

• Lamond, Angus I.; Earnshaw, WC (1998-04-24). "Structure and Function in the Nucleus". Science 280 (5363):547–553. doi:10.1126/science.280.5363.547. PMID 9554838.

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

• Pennisi E. (2004). "Evolutionary biology. The birth of the nucleus". Science 305 (5685): 766–768.doi:10.1126/science.305.5685.766. PMID 15297641.

A review article about the evolution of the nucleus, explaining a number of different theories• Pollard, Thomas D.; William C. Earnshaw (2004). Cell Biology. Philadelphia: Saunders. ISBN 0-7216-3360-9.

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 [68] Website covering structure and function of the nucleus from the Department of Oncology at

the University of Alberta.• The Nuclear Protein Database [69] Information on nuclear components.• The Nucleus Collection [70] in the Image & Video Library [71] of The American Society for Cell Biology [72]

contains peer-reviewed still images and video clips that illustrate the nucleus.• Nuclear Envelope and Nuclear Import Section [73] from Landmark Papers in Cell Biology [74], 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 [71] of The American Society for Cell Biology [72]

• Cytoplasmic patterns generated by human antibodies [75]

Cell nucleus 13

Gallery of nucleus images

Comparison of human and chimpanzeechromosomes.

Mousechromosometerritories indifferent cell

types.

24 chromosometerritories inhuman cells.

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Article Sources and Contributors 16

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Image Sources, Licenses and ContributorsImage:HeLa Hoechst 33258.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:HeLa_Hoechst_33258.jpg  License: unknown  Contributors: TenOfAllTradesImage:biological cell.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Biological_cell.svg  License: Creative Commons Attribution-Sharealike 2.5  Contributors: user:MesserWoland,user:Szczepan1990Image:Cell nucleus.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Cell_nucleus.jpg  License: Public Domain  Contributors: Nicolle Rager Fuller, National Science FoundationFile:Leeuwenhoek1719RedBloodCells.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Leeuwenhoek1719RedBloodCells.jpg  License: unknown  Contributors: Antoni vanLeeuwenhoekImage:Flemming1882Tafel1Fig14.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Flemming1882Tafel1Fig14.jpg  License: Public Domain  Contributors: Walther Flemming.Professor der Anatomie in Kiel.Image:Diagram human cell nucleus.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Diagram_human_cell_nucleus.svg  License: Public Domain  Contributors: user:LadyofHatsImage:NuclearPore crop.svg  Source: http://en.wikipedia.org/w/index.php?title=File:NuclearPore_crop.svg  License: Creative Commons Attribution-Sharealike 2.5  Contributors:User:Adenosine, User:LadyofHatsImage:MouseChromosomeTerritoriesBMC Cell Biol6-44Fig2e.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:MouseChromosomeTerritoriesBMC_Cell_Biol6-44Fig2e.jpg License: Creative Commons Attribution 2.0  Contributors: Robert Mayer, Alessandro Brero, Johann von Hase, Timm Schroeder, Thomas Cremer, Steffen DietzelImage:Micrograph of a cell nucleus.png  Source: http://en.wikipedia.org/w/index.php?title=File:Micrograph_of_a_cell_nucleus.png  License: Public Domain  Contributors: User:Opabiniaregalis, User:PNG crusade bot, User:Remember the dotFile:Transcription label en.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Transcription_label_en.jpg  License: GNU Free Documentation License  Contributors: InfoCan,TimVickersImage:RanGTPcycle.png  Source: http://en.wikipedia.org/w/index.php?title=File:RanGTPcycle.png  License: GNU Free Documentation License  Contributors: Original uploader was Shao atuk.wikipediaImage:Mitosis-flourescent.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Mitosis-flourescent.jpg  License: unknown  Contributors: -Image:redbloodcells.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Redbloodcells.jpg  License: unknown  Contributors: Habj, Ranveig, Shizhao, Simon Shek, Solon, Sundar,ThuressonImage:Chr2 orang human.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Chr2_orang_human.jpg  License: Creative Commons Attribution-Sharealike 2.5  Contributors: VerenaSchubel, Stefan Müller, Department Biologie der Ludwig-Maximilians-Universität München.Image:MouseChromosomeTerritoriesBMC Cell Biol6-44Fig2.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:MouseChromosomeTerritoriesBMC_Cell_Biol6-44Fig2.jpg License: Creative Commons Attribution 2.0  Contributors: Robert Mayer, Alessandro Brero, Johann von Hase, Timm Schroeder, Thomas Cremer, Steffen DietzelImage:PLoSBiol3.5.Fig1bNucleus46Chromosomes.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:PLoSBiol3.5.Fig1bNucleus46Chromosomes.jpg  License: unknown Contributors: Andreas Bolzer, Gregor Kreth, Irina Solovei, Daniela Koehler, Kaan Saracoglu, Christine Fauth, Stefan Müller, Roland Eils, Christoph Cremer, Michael R. Speicher, ThomasCremer

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