Mitosis

Overview
Mitosis is the process by which a cell duplicates the chromosomes in its cell nucleus, in order to generate two, identical, daughter nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two daughter cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define the mitotic (M) phase of the cell cycle, the division of the mother cell into two daughter cells, each with the genetic equivalent of the parent cell.

Mitosis occurs exclusively in eukaryotic cells, but occurs in different ways in different species. For example, animals undergo an "open" mitosis, where the nuclear envelope breaks down before the chromosomes separate, while yeast such as Saccharomyces cerevisiae  and fungi such as Aspergillus nidulans undergo a "closed" mitosis, where chromosomes divide within an intact cell nucleus. In multicellular organisms, the somatic cells undergo mitosis, while germ cells &mdash; cells destined to become sperm in males or ova in females &mdash; divide by a related process called meiosis. Prokaryotic cells, which lack a nucleus, divide by a process called binary fission.

The process of mitosis is complex and highly regulated. The sequence of events is divided into phases, 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 the process of mitosis the pairs of chromosomes 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.

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 different groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of fruit fly embryonic development. Errors in mitosis can either kill a cell through apoptosis or cause mutations that may lead to cancer.

The primary result of mitosis is the division of the parent cell's genome into two daughter cells. 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 S phase, in interphase, the period that precedes the mitotic phase in the cell cycle where preparation for mitosis occurs.

Each new chromosome now contains two identical copies of itself, called sister chromatids, attached together in a specialized region of the chromosome known as the centromere. Each sister chromatid is not considered a chromosome in itself, and a chromosome does not always contain two sister chromatids.

In most eukaryotes, the nuclear envelope that separates the DNA from the cytoplasm disassembles. 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. As a matter of convention, each sister chromatid is now considered a chromosome, so they are renamed to sister chromosomes. As the cell elongates, corresponding sister chromosomes are pulled toward opposite ends. A new nuclear envelope forms around the separated sister chromosomes.

As mitosis completes cytokinesis is well underway. In animal cells, the cell pinches inward where the imaginary line used to be, (the pinching of the cell membrane to form the two daughter cells is called 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 mother cell will be split in half, giving rise to two daughter cells, each with an equivalent and complete copy of the original genome.

Prokaryotic cells undergo a process similar to mitosis called binary fission. However, prokaryotes cannot be properly said to undergo mitosis because they lack a nucleus and only have a single chromosome with no centromere.

Interphase


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 divides (M).

Preprophase
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 plasmamembrane around the equatorial plane of the future mitotic spindle and predicting the position of cell plate fusion during telophase. The cells of higher plants (such as the flowering plants) lack centrioles. Instead, spindle microtubules aggregate on the surface of the nuclear envelope during prophase. The preprophase band disappears during nuclear envelope disassembly and spindle formation in prometaphase.

Prophase


Normally, the genetic material in the nucleus is in a loosely bundled coil called chromatin. At the onset of prophase, chromatin condenses together into a highly ordered structure called a chromosome. 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 cohesion complex. Chromosomes are visible at high magnification through a light microscope.

Close to the nucleus are two centrosomes. Each centrosome, which was replicated earlier independent of mitosis, acts as a coordinating center for the cell's microtubules. The two centrosomes nucleate microtubules (which may be thought of as cellular ropes or poles) by polymerizing soluble tubulin present in the cytoplasm. Molecular motor proteins create repulsive forces that will push the centrosomes to opposite side of the nucleus. The centrosomes are only present in animals. In plants the microtubules form independently.

Some centrosomes contain a pair of centrioles that may help organize microtubule assembly, but they are not essential to formation of the mitotic spindle.

Prometaphase


The nuclear envelope disassembles 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 envelope.

Each chromosome forms two kinetochores at the 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. Although the kinetochore structure and function are not fully understood, it is known that it contains some form of molecular motor. 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.

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. Prometaphase is sometimes considered part of prophase.



Metaphase


As microtubules find and attach to kinetochores in prometaphase, the centromeres of the chromosomes convene along the metaphase plate or equatorial plane, an imaginary line that is equidistant from the two centrosome poles. This even alignment is due to the counterbalance of the pulling powers generated by the opposing kinetochores, analogous to a tug-of-war between equally strong people. 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. Metaphase comes from the Greek μετα meaning "after."

Because proper chromosome separation requires that every kinetochore be attached to a bundle of microtubules (spindle fibers), 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.



Anaphase


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, allowing them to separate. These sister chromatids turned sister chromosomes are pulled apart by shortening kinetochore microtubules and move toward the respective centrosomes to which they are attached. Next, the nonkinetochore microtubules elongate, pushing the centrosomes (and the set of chromosomes to which they are attached) apart to opposite ends of the cell.

These two stages are sometimes called early and late anaphase. Early anaphase is usually defined as the separation of the sister chromatids, while late anaphase is the elongation of the microtubules and the microtubules being pulled farther apart. At the end of anaphase, the cell has succeeded in separating identical copies of the genetic material into two distinct populations.

Telophase


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 nonkinetochore microtubules continue to lengthen, elongating the cell even more. Corresponding sister chromosomes attach at opposite ends of the cell. A new nuclear envelope, using fragments of the parent cell's nuclear membrane, forms around each set of separated sister chromosomes. Both sets of chromosomes, now surrounded by new nuclei, unfold back into chromatin. Mitosis is complete, but cell division is not yet complete.

Cytokinesis
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. 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. 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. 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
The importance of mitosis is 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. Transcription is generally believed to cease during mitosis, but epigenetic mechanisms such as bookmarking function during this stage of the cell cycle to ensure that the "memory" of which genes were active prior to entry into mitosis are transmitted to the daughter cells.

Consequences of errors
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 coding for the same thing (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 aneuploidic cells and these abnormal cells can cause cancer.

Mitosis is a traumatic process. The cell 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 depend on the specific nature of the error. It may range from no noticeable effect, cancer induction, or organism death.

Endomitosis
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. An example of endomitosis would be what occurs in megakaryocytes to generate platelets within its cytoplasm.

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