Cell nucleus

nucleus with DNA stained blue. The distinct chromosome territories of chromosome 2 (red) and chromosome 9 (green) are shown using fluorescent in situ hybridization. The cell nucleus contains most of the cell's genetic material in the form of multiple linear DNA molecules organized into chromosomes. Each human cell contains roughly two meters of DNA. The other type, heterochromatin, is the more compact form, and contains DNA that is 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, in particular, 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. == Nuclear structures and landmarks ==

-studded outer nuclear membrane, nuclear pores, DNA (complexed as chromatin), and the nucleolus. The nucleus contains nearly all of the cell's DNA, surrounded by a network of fibrous intermediate filaments called the nuclear matrix, and is enveloped in a double membrane called the nuclear envelope. The nuclear envelope separates the fluid inside the nucleus, called the nucleoplasm, from the rest of the cell. The size of the nucleus is correlated to the size of the cell, and this ratio is reported across a range of cell types and species. In eukaryotes the nucleus in many cells typically occupies 10% of the cell volume. Together, these membranes serve to separate the cell's genetic material from the rest of the cell contents, and allow the nucleus to maintain an environment distinct from the rest of the cell. Despite their close apposition around much of the nucleus, the two membranes differ substantially in shape and contents. The inner membrane surrounds the nuclear content, providing its defining edge. The number of NPCs can vary considerably across cell types; small glial cells only have about a few hundred, with large Purkinje cells having around 20,000. The nuclear pore complex is composed of approximately thirty different proteins known as nucleoporins. 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 selectively allows the passage of small water-soluble molecules while preventing larger molecules, such as nucleic acids and larger proteins, from inappropriately entering or exiting the nucleus. These large molecules must be actively transported into the nucleus instead. 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, whereas 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 a ligand, many such receptors function as histone deacetylases that repress gene expression. The nuclear lamina is composed mostly of lamin proteins. Like all proteins, lamins are synthesized in the cytoplasm and later transported to the nucleus interior, where they are assembled before being incorporated into the existing network of nuclear lamina. Lamins found on the cytosolic face of the membrane, such as emerin and nesprin, bind to the cytoskeleton to provide structural support. 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. Lamin structures that make up the veil, such as LEM3, 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. Nucleolus of a cell nucleus, showing the darkly stained nucleolus The nucleolus is the largest of the discrete densely stained, membraneless structures known as nuclear bodies found in the nucleus. 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. In the first step of ribosome assembly, a protein called RNA polymerase I transcribes rDNA, which forms a large pre-rRNA precursor. This is cleaved into two large rRNA subunits – 5.8S, and 28S, and a small rRNA subunit 18S. 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. At the fluorescence-microscope level they appear as irregular, punctate structures, which vary in size and shape, and when examined by electron microscopy they are seen as clusters of interchromatin granules. Speckles are dynamic structures, and both their protein and RNA-protein components can cycle continuously between speckles and other nuclear locations, including active transcription sites. Speckles can work with p53 as enhancers of gene activity to directly enhance the activity of certain genes. Moreover, speckle-associating and non-associating p53 gene targets are functionally distinct. Studies on the composition, structure and behaviour of speckles have provided a model for understanding the functional compartmentalization of the nucleus and the organization of the gene-expression machinery splicing snRNPs and other splicing proteins necessary for pre-mRNA processing. The splicing speckles are also known as nuclear speckles (nuclear specks), splicing factor compartments (SF compartments), interchromatin granule clusters (IGCs), and B snurposomes. B snurposomes are found in the amphibian oocyte nuclei and in Drosophila melanogaster embryos. B snurposomes appear alone or attached to the Cajal bodies in the electron micrographs of the amphibian nuclei. While nuclear speckles were originally thought to be storage sites for the splicing factors, a more recent study demonstrated that organizing genes and pre-mRNA substrates near speckles increases the kinetic efficiency of pre-mRNA splicing, ultimately boosting protein levels by modulation of splicing. Cajal bodies and gems A nucleus typically contains between one and ten 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. 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. though it has also been suggested from microscopy evidence that CBs and gems are different manifestations of the same structure. Other nuclear bodies Beyond the nuclear bodies first described by Santiago Ramón y Cajal above (e.g., nucleolus, nuclear speckles, Cajal bodies) the nucleus contains a number of other nuclear bodies. These include polymorphic interphase karyosomal association (PIKA), promyelocytic leukaemia (PML) bodies, and paraspeckles. Although little is known about a number of these domains, they are significant in that they show that the nucleoplasm is not a uniform mixture, but rather contains organized functional subdomains. PIKA and PTF domains PIKA domains, or polymorphic interphase karyosomal associations, were first described in microscopy studies in 1991. Their function 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 small nuclear RNA (snRNA). PML-nuclear bodies Promyelocytic leukemia protein (PML-nuclear bodies) are spherical bodies found scattered throughout the nucleoplasm, measuring around 0.1–1.0 μm. They are known by a number of other names, including nuclear domain 10 (ND10), Kremer bodies, and PML oncogenic domains. PML-nuclear bodies are named after one of their major components, the promyelocytic leukemia protein (PML). They are often seen in the nucleus in association with Cajal bodies and cleavage bodies. Paraspeckles Discovered by Fox et al. in 2002, paraspeckles are irregularly shaped compartments in the interchromatin space of the nucleus. 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. that is involved in the regulation of gene expression. Furthermore, paraspeckles are dynamic structures that are altered in response to changes in cellular metabolic activity. They are transcription dependent This name is derived from the Greek klastos (κλαστός), broken and soma (σῶμα), body. The scarcity of clastosomes in cells indicates that they are not required for proteasome function. Osmotic stress has also been shown to cause the formation of clastosomes. These nuclear bodies contain catalytic and regulatory subunits of the proteasome and its substrates, indicating that clastosomes are sites for degrading proteins. == Function ==

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. The main function of the cell nucleus is to control gene expression and mediate the replication of DNA during the cell cycle. 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. 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 malformed and nonfunctional proteins. Gene expression during transcription, highlighting the possibility of transcribing more than one gene at a time. The diagram includes 8 RNA polymerases however the number can vary depending on cell type. The image also includes transcription factors and a porous, protein core. 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 that either directly mediate transcription or are involved in regulating the process. These proteins include helicases, which unwind the double-stranded DNA molecule to facilitate access to it, RNA polymerases, which bind to the DNA promoter to synthesize the growing RNA molecule, topoisomerases, which 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 cytoplasm 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-transcriptional modification. The 3' poly-adenine tail is only added after transcription is complete. == Dynamics and regulation ==

Nuclear transport s, such as RNA and proteins, are actively transported across the nuclear membrane in a process called the Ran-GTP nuclear transport cycle. 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 (GTP) to release energy. The key GTPase in nuclear transport is Ran, which is bound to 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. 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 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. Therefore, the early stages in the cell cycle, beginning in prophase and until around prometaphase, the nuclear membrane is dismantled. 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. 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. == Nuclei per cell ==

Most eukaryotic cell types usually have a single nucleus, but some have no nuclei, while others have several. This can result from normal development, as in the maturation of mammalian red blood cells, or from faulty cell division. Anucleated cells An anucleated cell contains no nucleus and is, 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 through 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, which is 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 has two nuclei. In flowering plants, this condition occurs in sieve tube elements. Multinucleated cells Multinucleated cells contain multiple nuclei. Most acantharean species of protozoa and some fungi in mycorrhizae have naturally multinucleated cells. Other examples include the intestinal parasites in the genus Giardia, which have two nuclei per cell. Ciliates have two kinds of nuclei in a single cell, a somatic macronucleus and a germline micronucleus. In humans, skeletal muscle cells, also called myocytes and syncytium, become multinucleated during development; the resulting arrangement of nuclei near the periphery of the cells allows maximal intracellular space for myofibrils. and are also implicated in tumor formation. A number of dinoflagellates are known to have two nuclei. Unlike other multinucleated cells these nuclei contain two distinct lineages of DNA: one from the dinoflagellate and the other from a symbiotic diatom. == Evolution ==

As the major defining characteristic of the eukaryotic cell, the nucleus's evolutionary origin has been the subject of much speculation. Four major hypotheses have been proposed to explain the existence of the nucleus, although none have yet earned widespread support. The first model known as the "syntrophic model" proposes that a symbiotic relationship between the archaea and bacteria created the nucleus-containing eukaryotic cell. (Organisms of the Archaeal and Bacterial domains have no cell nucleus.) 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. One possibility is that the nuclear membrane arose as a new membrane system following the origin of mitochondria in an archaebacterial host. The nuclear membrane may have served to protect the genome from damaging reactive oxygen species produced by the protomitochondria. 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 Planctomycetota bacteria that possess a nuclear structure with primitive pores and other compartmentalized membrane structures. A similar proposal states that a eukaryote-like cell, the hypothetical 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. A more recent proposal, 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. == History ==

, 1719 '' salivary gland cell published by Walther Flemming in 1882. The nucleus contains polytene chromosomes. The nucleus was the first organelle to be discovered. What is most likely the oldest preserved drawing dates back to the early microscopist Antonie van Leeuwenhoek (1632–1723). He observed a "lumen", the nucleus, in the red blood cells of salmon. Unlike mammalian red blood cells, those of other vertebrates still contain nuclei. The nucleus was also described by Franz Bauer in 1804 and in more detail in 1831 by Scottish botanist Robert Brown in a talk at the Linnean Society of London. Brown was studying orchids under the microscope 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 (""). The function of the nucleus remained unclear. Between 1877 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 protoplasm ("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, including amphibians and molluscs. Eduard Strasburger produced the same results for plants in 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 therefore developed. == See also ==