Why mitosis

Fusion of the sex cells creates a new individual with two copies of each chromosome. Many single-celled organisms reproduce by cell division and have a single copy of each chromosome.

We now know that centrioles duplicate during S phase, although many details of this duplication process are still under investigation. It is now well-established that spindles are bipolar arrays of microtubules composed of tubulin Figure 5 and that the centrosomes nucleate the growth of the spindle microtubules.

During mitosis, many of the spindle fibers attach to chromosomes at their kinetochores Figure 6 , which are specialized structures in the most constricted regions of the chromosomes. The length of these kinetochore-attached microtubules then decreases during mitosis, pulling sister chromatids to opposite poles of the spindle. Other spindle fibers do not attach to chromosomes, but instead form a scaffold that provides mechanical force to separate the daughter nuclei at the end of mitosis.

From his many detailed drawings of mitosen, Walther Flemming correctly deduced, but could not prove, the sequence of chromosome movements during mitosis Figure 7. Flemming divided mitosis into two broad parts: a progressive phase, during which the chromosomes condensed and aligned at the center of the spindle, and a regressive phase, during which the sister chromatids separated.

Our modern understanding of mitosis has benefited from advances in light microscopy that have allowed investigators to follow the process of mitosis in living cells. Such live cell imaging not only confirms Flemming's observations, but it also reveals an extremely dynamic process that can only be partially appreciated in still images.

Mitosis begins with prophase, during which chromosomes recruit condensin and begin to undergo a condensation process that will continue until metaphase. In most species , cohesin is largely removed from the arms of the sister chromatids during prophase, allowing the individual sister chromatids to be resolved. Cohesin is retained, however, at the most constricted part of the chromosome, the centromere Figure 9.

During prophase, the spindle also begins to form as the two pairs of centrioles move to opposite poles and microtubules begin to polymerize from the duplicated centrosomes. Prometaphase begins with the abrupt fragmentation of the nuclear envelope into many small vesicles that will eventually be divided between the future daughter cells.

The breakdown of the nuclear membrane is an essential step for spindle assembly. Because the centrosomes are located outside the nucleus in animal cells, the microtubules of the developing spindle do not have access to the chromosomes until the nuclear membrane breaks apart.

Prometaphase is an extremely dynamic part of the cell cycle. Microtubules rapidly assemble and disassemble as they grow out of the centrosomes, seeking out attachment sites at chromosome kinetochores, which are complex platelike structures that assemble during prometaphase on one face of each sister chromatid at its centromere.

As prometaphase ensues, chromosomes are pulled and tugged in opposite directions by microtubules growing out from both poles of the spindle, until the pole-directed forces are finally balanced. Sister chromatids do not break apart during this tug-of-war because they are firmly attached to each other by the cohesin remaining at their centromeres. At the end of prometaphase, chromosomes have a bi-orientation, meaning that the kinetochores on sister chromatids are connected by microtubules to opposite poles of the spindle.

Next, chromosomes assume their most compacted state during metaphase, when the centromeres of all the cell's chromosomes line up at the equator of the spindle. Metaphase is particularly useful in cytogenetics , because chromosomes can be most easily visualized at this stage. Furthermore, cells can be experimentally arrested at metaphase with mitotic poisons such as colchicine. Video microscopy shows that chromosomes temporarily stop moving during metaphase.

A complex checkpoint mechanism determines whether the spindle is properly assembled, and for the most part, only cells with correctly assembled spindles enter anaphase. Figure 10 Figure Detail. Figure 9. The progression of cells from metaphase into anaphase is marked by the abrupt separation of sister chromatids.

A major reason for chromatid separation is the precipitous degradation of the cohesin molecules joining the sister chromatids by the protease separase Figure Two separate classes of movements occur during anaphase. During the first part of anaphase, the kinetochore microtubules shorten, and the chromosomes move toward the spindle poles.

During the second part of anaphase, the spindle poles separate as the non-kinetochore microtubules move past each other. These latter movements are currently thought to be catalyzed by motor proteins that connect microtubules with opposite polarity and then "walk" toward the end of the microtubules. Mitosis ends with telophase, or the stage at which the chromosomes reach the poles. The nuclear membrane then reforms, and the chromosomes begin to decondense into their interphase conformations.

Telophase is followed by cytokinesis, or the division of the cytoplasm into two daughter cells. The daughter cells that result from this process have identical genetic compositions. Cheeseman, I. Molecular architecture of the kinetochore-microtubule interface. Nature Reviews Molecular Cell Biology 9 , 33—46 doi Cremer, T. Chromosome territories, nuclear architecture and gene regulation in mammalian cells. Prophase : The chromosomes coil and shorten, and become visible. It becomes apparent that the chromosomes have duplicated.

Pairs of identical chromosomes remain attached to each other at the centromere and each chromosome is called a chromatid. Metaphase : Chromosomes line up along the center of the cell. Walther Flemming: pioneer of mitosis research. Nature Reviews Molecular Cell Biology 2, 72 All rights reserved.

Prophase is the first stage in mitosis, occurring after the conclusion of the G 2 portion of interphase. During prophase, the parent cell chromosomes — which were duplicated during S phase — condense and become thousands of times more compact than they were during interphase.

Because each duplicated chromosome consists of two identical sister chromatids joined at a point called the centromere , these structures now appear as X-shaped bodies when viewed under a microscope.

Several DNA binding proteins catalyze the condensation process, including cohesin and condensin. Cohesin forms rings that hold the sister chromatids together, whereas condensin forms rings that coil the chromosomes into highly compact forms. The mitotic spindle also begins to develop during prophase. As the cell's two centrosomes move toward opposite poles, microtubules gradually assemble between them, forming the network that will later pull the duplicated chromosomes apart.

When prophase is complete, the cell enters prometaphase — the second stage of mitosis. During prometaphase, phosphorylation of nuclear lamins by M-CDK causes the nuclear membrane to break down into numerous small vesicles. As a result, the spindle microtubules now have direct access to the genetic material of the cell. As prometaphase ends and metaphase begins, the chromosomes align along the cell equator. Every chromosome has at least two microtubules extending from its kinetochore — with at least one microtubule connected to each pole.

At this point, the tension within the cell becomes balanced, and the chromosomes no longer move back and forth. In addition, the spindle is now complete, and three groups of spindle microtubules are apparent.

Kinetochore microtubules attach the chromosomes to the spindle pole; interpolar microtubules extend from the spindle pole across the equator, almost to the opposite spindle pole; and astral microtubules extend from the spindle pole to the cell membrane.

Metaphase leads to anaphase , during which each chromosome's sister chromatids separate and move to opposite poles of the cell. Enzymatic breakdown of cohesin — which linked the sister chromatids together during prophase — causes this separation to occur.

Upon separation, every chromatid becomes an independent chromosome. Meanwhile, changes in microtubule length provide the mechanism for chromosome movement. More specifically, in the first part of anaphase — sometimes called anaphase A — the kinetochore microtubules shorten and draw the chromosomes toward the spindle poles.

Then, in the second part of anaphase — sometimes called anaphase B — the astral microtubules that are anchored to the cell membrane pull the poles further apart and the interpolar microtubules slide past each other, exerting additional pull on the chromosomes Figure 2.