Mitosis divides the chromosomes in a cell nucleus.

Allium cells in different phases of the cell cycle, some in mitosis.

Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly equal shares of these cellular components. ^[1] Mitosis and cytokinesis together define the mitotic (M) phase of the cell cycle—the division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell. This accounts for approximately 10% of the cell cycle.

Mitosis occurs only in eukaryotic cells and the process varies in different species. For example, animals undergo an "open" mitosis, where the nuclear envelope breaks down before the chromosomes separate, while fungi such as Aspergillus nidulans and Saccharomyces cerevisiae (yeast) undergo a "closed" mitosis, where chromosomes divide within an intact cell nucleus.^[2] Prokaryotic cells, which lack a nucleus, divide by a process called binary fission.

The process of mitosis is fast and highly complex. The sequence of events is divided into stages corresponding to the completion of one set of activities and the start of the next. These stages are prophase, prometaphase, metaphase, anaphase and telophase. During mitosis the pairs of chromatids condense and attach to fibers that pull the sister chromatids to opposite sides of the cell. The cell then divides in cytokinesis, to produce two identical daughter cells which are still diploid cells.^[3]

Because cytokinesis usually occurs in conjunction with mitosis, "mitosis" is often used interchangeably with "mitotic phase". However, there are many cells where mitosis and cytokinesis occur separately, forming single cells with multiple nuclei. This occurs most notably among the fungi and slime moulds, but is found in various groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of fruit fly embryonic development.^[4] Errors in mitosis can either kill a cell through apoptosis or cause mutations that may lead to certain types of cancer.

Overview of Cell Cycle in Relation to Mitosis[link]

The primary result of mitosis is the transferring of the parent cell's genome into two daughter cells. These two cells are identical and do not differ in any way from the original parent cell. The genome is composed of a number of chromosomes—complexes of tightly-coiled DNA that contain genetic information vital for proper cell function. Because each resultant daughter cell should be genetically identical to the parent cell, the parent cell must make a copy of each chromosome before mitosis. This occurs during the S phase of interphase, the period that precedes the mitotic phase in the cell cycle where preparation for mitosis occurs.^[5]

Each chromosome now has an identical copy of itself, and together the two are called sister chromatids. The sister chromatids are held together by a specialized region of the chromosome: a DNA sequence called the centromere.

The "real" process of mitosis begins when the chromosomes condense and become visible. In most eukaryotes, the nuclear membrane which segregates the DNA from the cytoplasm disintegrates into membrane vesicles. The nucleolus which make ribosomes in the cell also dissolves. The chromosomes align themselves in a line spanning the cell. Microtubules — essentially miniature strings— splay out from opposite ends of the cell and shorten, pulling apart the sister chromatids of each chromosome.^[6] As a matter of convention, each sister chromatid is now considered a chromosome, so they are renamed to daughter chromosomes. As the cell elongates, corresponding daughter chromosomes are pulled toward opposite ends. A new nuclear membrane forms around the separated daughter chromosomes.

As mitosis completes,the cell begins cytokinesis. In animal cells, the cell pinches inward where the imaginary line used to be (the area of the cell membrane that pinches to form the two daughter cells is called the cleavage furrow), separating the two developing nuclei. In plant cells, the daughter cells will construct a new dividing cell wall between each other. Eventually, the parent cell will be split in half, giving rise to two daughter cells, each with a replica of the original genome.

Prokaryotic cells undergo a process similar to mitosis called binary fission. However, the process of binary fission is very much different from the process of mitosis, because of the non-involvement of nuclear dynamics and lack of linear chromosomes.^[7]

Phases of cell cycle and mitosis[link]

Interphase[link]

The cell cycle

The mitotic phase is a relatively short period of the cell cycle. It alternates with the much longer interphase, where the cell prepares itself for cell division. Interphase is divided into three phases: G₁ (first gap), S (synthesis), and G₂ (second gap). During all three phases, the cell grows by producing proteins and cytoplasmic organelles. However, chromosomes are replicated only during the S phase. Thus, a cell grows (G₁), continues to grow as it duplicates its chromosomes (S), grows more and prepares for mitosis (G₂), and finally it divides (M) before restarting the cycle.^[5] All these phases in the interphase are highly regulated, mainly via proteins. The phases follow one another in strict order and there are "checkpoints" that give the cell the cues to proceed from one phase to another. There is also a fourth section in Interphase where the cell has the option to enter G₀. Cells continue on through this cell cycle until they become too crowded; at that point they will exit the cell cycle and enter G₀. This reaction is called contact inhibition or density-dependent inhibition. Altogether interphase takes up roughly 90% of a cell's lifespan.

Preprophase[link]

In plant cells only, prophase is preceded by a pre-prophase stage. In highly vacuolated plant cells, the nucleus has to migrate into the center of the cell before mitosis can begin. This is achieved through the formation of a phragmosome, a transverse sheet of cytoplasm that bisects the cell along the future plane of cell division. In addition to phragmosome formation, preprophase is characterized by the formation of a ring of microtubules and actin filaments (called preprophase band) underneath the plasma membrane around the equatorial plane of the future mitotic spindle. This band marks the position where the cell will eventually divide. The cells of higher plants (such as the flowering plants) lack centrioles; instead, microtubules form a spindle on the surface of the nucleus and are then organized into a spindle by the chromosomes themselves, after the nuclear membrane dissolves.^[8] The preprophase band disappears during nuclear membrane dissolution and spindle formation in prometaphase.^[9]

Prophase: The two round objects above the nucleus are the centrosomes. The chromatin is condensing into chromosomes.   Prometaphase: The nuclear membrane disintegrates, and microtubules have invaded the nuclear space. These microtubules can attach to kinetochores or they can interact with opposing microtubules.   Metaphase: The chromosomes align at the metaphase plate.   Anaphase: The chromosomes split and the kinetochore microtubules shorten.   Telophase: The decondensing chromosomes are surrounded by nuclear membranes. Cytokinesis has already begun; the pinched area is known as the cleavage furrow.

Prophase[link]

Micrograph showing condensed chromosomes in blue and the mitotic spindle in green during prometaphase of mitosis

Normally, the genetic material in the nucleus is in a loosely bundled coil called chromatin. At the onset of prophase, chromatin fibers become tightly coiled, condensing into discrete chromosomes. It is crucial for the reader to note that chromatin is a complex consisting of both chromosomes and specific proteins. Since the genetic material has already been duplicated earlier in S phase, the replicated chromosomes have two sister chromatids, bound together at the centromere by the cohesin protein complex. Chromosomes are typically visible at high magnification through a light microscope.

Also inside the nucleus, the nucleolus in the nucleus disappears from view. This is noteworthy because the cell does not need to divide the nucleolus right away. It will later reform when the nucleus divides completely.

Close to the nucleus are structures called centrosomes, consisting of a pair of centrioles, and actin, a halo of microtubule fragments, centrioles are found in most eukaryotic animal cells. The centrosome is the coordinating center for the cell's microtubules. A cell inherits a single centrosome at cell division, which is replicated by the cell with the help of the nucleus before a new mitosis begins, giving a pair of centrosomes. The two centrosomes nucleate microtubules (which may be thought of as cellular ropes or poles) to form the spindle by polymerizing soluble tubulin. Molecular motor proteins then push the centrosomes along these microtubules to opposite sides of the cell. Although centrioles help organize microtubule assembly, they are not essential for the formation of the spindle, since they are absent from plants,^[8] and centrosomes are not always used in mitosis.^[10]

Prometaphase[link]

Prometaphase is sometimes included as part of the end of prophase and early metaphase, but we decide to use the real prometaphase in this section.

During early prometaphase, the nuclear membrane disintegrates and microtubules invade the nuclear space. This is called open mitosis, and it occurs in most multicellular organisms. Fungi and some protists, such as algae or trichomonads, undergo a variation called closed mitosis where the spindle forms inside the nucleus, or its microtubules are able to penetrate an intact nuclear membrane, which stays intact.^[11][12]

In late prometaphase, each chromosome forms two kinetochores at its centromere, one attached at each chromatid. A kinetochore is a complex protein structure that is analogous to a ring for the microtubule hook; it is the point where microtubules attach themselves to the chromosome ( about 1-40 in number, on an average 20 ).^[13] Although the kinetochore structure and function are not fully understood, it is known that it contains some form of molecular motor.^[14] When a microtubule connects with the kinetochore, the motor activates, using energy from ATP to "crawl" up the tube toward the originating centrosome. This motor activity, coupled with polymerisation and depolymerisation of microtubules, provides the pulling force necessary to later separate the chromosome's two chromatids.^[14]

When the spindle grows to sufficient length, kinetochore microtubules begin searching for kinetochores to attach to. A number of nonkinetochore microtubules find and interact with corresponding nonkinetochore microtubules from the opposite centrosome to form the mitotic spindle.^[15] Prometaphase is sometimes considered part of prophase.

In the fishing pole analogy, the kinetochore would be the "hook" that catches a sister chromatid or "fish". The centrosome acts as the "reel" that draws in the spindle fibers or "fishing line". It is also one of the main phases of mitosis because without it cytokinesis would not be able to occur.

Metaphase[link]

A cell in late metaphase. All chromosomes (blue) but one have arrived at the metaphase plate.

Metaphase comes from the Greek μετα meaning "after." Microtubules find and attach to kinetochores in prometaphase. Then the two centrosomes start pulling the chromosomes through their attached centromeres towards the two ends of the cell. As a result, the chromosomes come under longitudinal tension from the two ends of the cell. The centromeres of the chromosomes, in some sense, convene along the metaphase plate or equatorial plane, an imaginary line that is equidistant from the two centrosome poles.^[15] This line is called the spindle equator. This even alignment is due to the counterbalance of the pulling powers generated by the opposing kinetochores, analogous to a tug-of-war between people of equal strength. In certain types of cells, chromosomes do not line up at the metaphase plate and instead move back and forth between the poles randomly, only roughly lining up along the midline.

Because proper chromosome separation requires that every kinetochore be attached to a bundle of microtubules (spindle fibres), it is thought that unattached kinetochores generate a signal to prevent premature progression to anaphase without all chromosomes being aligned. The signal creates the mitotic spindle checkpoint.^[16]

Anaphase[link]

When every kinetochore is attached to a cluster of microtubules and the chromosomes have lined up along the metaphase plate, the cell proceeds to anaphase (from the Greek ανα meaning “up,” “against,” “back,” or “re-”).

Two events then occur: first, the proteins that bind sister chromatids together are cleaved. These sister chromatids now become separate daughter chromosomes, and are pulled apart by shortening kinetochore microtubules and move toward the respective centrosomes to which they are attached.

Next, the polar microtubules elongate, pulling the centrosomes (and the set of chromosomes to which they are attached) apart to opposite ends of the cell. The force that causes the centrosomes to move towards the ends of the cell is still unknown, although there is a theory that suggests that the rapid assembly and breakdown of microtubules may cause this movement. At the end of anaphase the kinecticore microtubules all degrade, and of course, the cell begins to elongate like a killer T-cell in action.^[17]

Telophase[link]

Telophase (from the Greek τελος meaning "end") is a reversal of prophase and prometaphase events. It "cleans up" the after effects of mitosis. At telophase, the polar microtubules continue to lengthen, elongating the cell even more. Corresponding daughter chromosomes attach at opposite ends of the cell. A new nuclear membrane, using the membrane vesicles of the parent cell's old nuclear membrane, forms around each set of separated daughter chromosomes. (the membrane does not enclose the centrosome, though!) The nucleoli reappear, too. Both sets of chromosomes, now surrounded by new nuclei, begin to "relax" or decondense back into chromatin. Mitosis is complete, but cell division is not yet complete.

Cytokinesis[link]

Cilliate undergoing cytokinesis, with the cleavage furrow being clearly visible

Cytokinesis is often mistakenly thought to be the final part of telophase; however, cytokinesis is a separate process that begins at the same time as telophase. Cytokinesis is technically not even a phase of mitosis, but rather a separate process, necessary for completing cell division. In animal cells, a cleavage furrow (pinch) containing a contractile ring develops where the metaphase plate used to be, pinching off the separated nuclei.^[18] In both animal and plant cells, cell division is also driven by vesicles derived from the Golgi apparatus, which move along microtubules to the middle of the cell.^[19] In plants this structure coalesces into a cell plate at the center of the phragmoplast and develops into a cell wall, separating the two nuclei. The phragmoplast is a microtubule structure typical for higher plants, whereas some green algae use a phycoplast microtubule array during cytokinesis.^[20] Each daughter cell has a complete copy of the genome of its parent cell. The end of cytokinesis marks the end of the M-phase.

Significance[link]

Mitosis is important for the maintenance of the chromosomal set; each cell formed receives chromosomes that are alike in composition and equal in number to the chromosomes of the parent cell.

Mitosis occurs in the following circumstances:

Development and growth

The number of cells within an organism increases by mitosis. This is the basis of the development of a multicellular body from a single cell i.e., zygote and also the basis of the growth of a multicellular body.

Cell replacement

In some parts of body, e.g. skin and digestive tract, cells are constantly sloughed off and replaced by new ones. New cells are formed by mitosis and so are exact copies of the cells being replaced. Similarly, RBCs have short life span (only about 4 months) and new RBCs are formed by mitosis.

Regeneration

Some organisms can regenerate body parts. The production of new cells in such instances is achieved by mitosis. For example, starfish regenerate lost arms through mitosis.

Asexual reproduction

Some organisms produce genetically similar offspring through asexual reproduction. For example, the hydra reproduces asexually by budding. The cells at the surface of hydra undergo mitosis and form a mass called a bud. Mitosis continues in the cells of the bud and this grows into a new individual. The same division happens during asexual reproduction or vegetative propagation in plants.

Consequences of errors[link]

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An abnormal (tripolar) mitoses (12 o'clock position) in a precancerous lesion of the stomach. H&E stain

Although errors in mitosis are rare, the process may go wrong, especially during early cellular divisions in the zygote. Mitotic errors can be especially dangerous to the organism because future offspring from this parent cell will carry the same disorder.

In non-disjunction, a chromosome may fail to separate during anaphase. One daughter cell will receive both sister chromosomes and the other will receive none. This results in the former cell having three chromosomes containing the same genes (two sisters and a homologue), a condition known as trisomy, and the latter cell having only one chromosome (the homologous chromosome), a condition known as monosomy. These cells are considered aneuploid, a condition often associated with cancer.^[21] Occasionally when cells experience nondisjunction, they fail to complete cell division and retain both nuclei in one cell, resulting in binucleated cells.

Mitosis is a demanding process for the cell, which goes through dramatic changes in ultrastructure, its organelles disintegrate and reform in a matter of hours, and chromosomes are jostled constantly by probing microtubules. Occasionally, chromosomes may become damaged. An arm of the chromosome may be broken and the fragment lost, causing deletion. The fragment may incorrectly reattach to another, non-homologous chromosome, causing translocation. It may reattach to the original chromosome, but in reverse orientation, causing inversion. Or, it may be treated erroneously as a separate chromosome, causing chromosomal duplication. The effect of these genetic abnormalities depends on the specific nature of the error.

When mutations occur in the genes that control the timing and number of mitotic cell cycles, cells may lose control of nuclear replication and cellular division. This can result in abnormal cell growth and the synthesis of excess tissue in a single organ. The excess tissue is a cancerous cell mass known as a tumor. Tumors that remain in their original location are called benign tumors and may not be harmful if they do not grow to excessive sizes. Tumors that leave their original location and invade other cells there are called malignant tumors. The migrating tumor cells may lodge in other parts of the body and form new tumors in a process known as metastasis.

Endomitosis[link]

Endomitosis is a variant of mitosis without nuclear or cellular division, resulting in cells with many copies of the same chromosome occupying a single nucleus. This process may also be referred to as endoreduplication and the cells as endoploid.^[4] An example of a cell that goes through endomitosis is the megakaryocyte.^[22]

Timeline in pictures[link]

Real mitotic cells can be visualized through the microscope by staining them with fluorescent antibodies and dyes. These light micrographs are included below.

• 

  Early prophase: Nonkinetochore microtubules, shown as green strands, have established a matrix around the degrading nucleus, in blue. The green nodules are the centrosomes.

• 

  Early prometaphase: The nuclear membrane has just degraded, allowing the microtubules to quickly interact with the kinetochores on the chromosomes, which have just condensed.

• 

  Late metaphase: The centrosomes have moved to the poles of the cell and have established the mitotic spindle. The chromosomes, in light blue, have all assembled at the metaphase plate, except for one.

• 

  Anaphase: Lengthening nonkinetochore microtubules push the two sets of chromosomes further apart.

See also[link]

• Meiosis
• Mitogen
• Cytoskeleton
• Motor protein
• Aneuploidy
• Chromosomal disorder
• Binary fission

References[link]

Cited texts[link]

• Raven PH, Evert RF, Eichhorn SE. (2005). Biology of Plants (7th ed.). New York: W.H. Freeman and Company Publishers. ISBN 0-7167-1007-2. 

Further reading[link]

• Morgan, David L. (2007). The cell cycle: principles of control. London: Published by New Science Press in association with Oxford University Press. ISBN 0-9539181-2-2. 
• Alberts B, Johnson A, Lewis J, Raff M, Roberts K, and Walter P (2002). "Mitosis". Molecular Biology of the Cell. Garland Science. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=mitosis&rid=mboc4.section.3349. Retrieved 2006-01-22. 
• Campbell, N. and Reece, J. (December 2001). "The Cell Cycle". Biology (6th ed.). San Francisco: Benjamin Cummings/Addison-Wesley. pp. 217–224. ISBN 0-8053-6624-5. 
• Cooper, G. (2000). "The Events of M Phase". The Cell: A Molecular Approach. Sinaeur Associates, Inc. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=M%20Phase,Events&rid=cooper.section.2470. Retrieved 2006-01-22. 
• Freeman, S (2002). "Cell Division". Biological Science. Upper Saddle River, NJ: Prentice Hall. pp. 155–174. ISBN 0-13-081923-9. 
• Lodish H, Berk A, Zipursky L, Matsudaira P, Baltimore D, Darnell J (2000). "Overview of the Cell Cycle and Its Control". Molecular Cell Biology. W.H. Freeman. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=Overview,Control,Cell+Cycle&rid=mcb.section.3463. Retrieved 2006-01-22. 

External links[link]

Wikimedia Commons has media related to: Mitosis

• Mitosis Animation.
• Mitosis (Flash Animation)
• Video of a live amphibian lung cell undergoing mitosis.
• A Flash animation comparing Mitosis and Meiosis
• Animation from the Life Sciences Dept of University of North Texas
• Khan Academy, lecture
• Studying Mitosis in Cultured Mammalian Cells
• General K-12 classroom resources for Mitosis
• CCO The Cell-Cycle Ontology
• WormWeb.org: Interactive Visualization of the C. elegans Cell Lineage - Visualize the entire cell lineage tree and all of the cell divisions of the nematode C. elegans