12.2 Mitosis and cytokinesis

Mitosis ensures accurate distribution of genetic material during cell division. This process involves chromosome condensation, spindle formation, and precise segregation of sister chromatids. Understanding mitosis is crucial for grasping how cells maintain their genetic integrity.

Cytokinesis completes cell division by physically separating daughter cells. While animal cells use a contractile ring, plant cells form a cell plate. Errors in mitosis or cytokinesis can lead to aneuploidy, potentially causing developmental disorders or contributing to cancer progression.

Mitosis and Chromosome Segregation

Stages of mitosis

Each stage of mitosis has a distinct job in getting chromosomes sorted and delivered to two new cells. Here's what happens at each step:

• Prophase
  • Chromatin condenses into tightly coiled, visible chromosomes (the familiar X-shaped structures you see in diagrams are actually pairs of sister chromatids joined at the centromere)
  • The nuclear envelope breaks down, exposing chromosomes to cytoplasmic components like spindle microtubules
  • Centrosomes, the main microtubule-organizing centers, migrate to opposite poles of the cell (in animal cells; plant cells lack centrosomes but still form spindles)
  • The mitotic spindle, a bipolar array of microtubules, begins to assemble between the separating centrosomes
• Metaphase
  • Chromosomes align at the cell's equatorial plane, forming the metaphase plate (an imaginary plane, not a physical structure)
  • Kinetochores, protein complexes assembled on the centromere of each sister chromatid, attach to microtubules from opposite spindle poles. This arrangement, called amphitelic attachment, is the only correct configuration
  • The spindle assembly checkpoint (covered below) verifies that every chromosome is properly attached before the cell proceeds
• Anaphase
  • The enzyme separase cleaves the cohesin proteins holding sister chromatids together
  • Sister chromatids separate and move toward opposite poles, now considered individual chromosomes
  • Kinetochore microtubules shorten (depolymerize) at both ends, pulling chromosomes poleward at roughly 1–2 μm/min in human cells
  • Simultaneously, polar microtubules elongate, pushing the two poles farther apart (this is why the cell visibly stretches during anaphase)
• Telophase
  • Chromosomes arrive at the spindle poles and begin to decondense back into diffuse chromatin
  • A nuclear envelope re-forms around each chromosome set, producing two distinct nuclei
  • The mitotic spindle disassembles as its microtubules depolymerize
  • Cytokinesis typically begins during telophase, overlapping with the final steps of mitosis

Role of the mitotic spindle

The spindle is the machinery that physically moves chromosomes. Without it, there's no way to ensure each daughter cell gets exactly one copy of every chromosome.

• Microtubules are polymers of $\alpha$- and $\beta$-tubulin dimers. They have an inherent polarity: a fast-growing plus end (typically pointed toward the cell center) and a slower-growing minus end (anchored at the centrosome).
• Three classes of spindle microtubules do different jobs:
  • Kinetochore microtubules connect kinetochores on chromosomes to spindle poles. These are the ones that pull sister chromatids apart in anaphase.
  • Polar (interpolar) microtubules extend from opposite poles and overlap at the cell equator. Motor proteins (mainly kinesin-5) cross-link these overlapping microtubules and slide them apart, helping elongate the spindle.
  • Astral microtubules radiate outward from centrosomes toward the cell cortex, helping position the spindle within the cell.
• Motor proteins generate the forces for chromosome movement:
  • Dynein walks toward the minus end (poleward), contributing to pulling chromosomes toward the poles
  • Kinesins walk toward the plus end and serve various roles, including pushing poles apart and congressing chromosomes to the metaphase plate
• Microtubule dynamic instability (constant switching between polymerization and depolymerization) is itself a force-generating mechanism. As kinetochore microtubules depolymerize at the plus end, they pull the attached chromosome poleward. This is sometimes called the "Pac-Man" mechanism because the kinetochore appears to chew its way along the shrinking microtubule.

Cytokinesis and Mitotic Errors

Cytokinesis in animals vs. plants

Mitosis divides the nucleus, but cytokinesis divides everything else. The mechanism differs significantly between animal and plant cells because plant cells have a rigid cell wall.

Animal cells:

1. A cleavage furrow forms at the cell equator, perpendicular to the spindle axis
2. A contractile ring of actin and myosin II filaments assembles just beneath the plasma membrane
3. The ring contracts, constricting the cell inward like a drawstring bag
4. The furrow deepens until only a thin bridge, the midbody, connects the two daughter cells
5. The midbody is severed in a final step called abscission, completing separation

Plant cells:

1. A phragmoplast, a structure built from microtubules and actin filaments, forms between the two new nuclei
2. Golgi-derived vesicles carrying cell wall materials (cellulose, hemicellulose, pectin) are transported along phragmoplast microtubules to the cell center
3. These vesicles fuse to form the cell plate, a new partition between daughter cells
4. The cell plate grows outward (centrifugally) until it reaches and fuses with the existing parent cell wall
5. The cell plate matures into a new segment of cell wall with plasma membrane on each side

The key difference: animal cells pinch inward from the outside, while plant cells build a wall outward from the center.

Consequences of mitotic errors

When chromosome segregation goes wrong, the result is aneuploidy, an abnormal number of chromosomes in daughter cells. Two common mechanisms cause this:

• Nondisjunction: sister chromatids fail to separate during anaphase, so one daughter cell gains an extra chromosome and the other loses one
• Anaphase lag: a chromosome moves too slowly (often due to improper kinetochore attachment) and gets left out of both daughter nuclei

Aneuploidy has serious consequences:

• Down syndrome (trisomy 21): three copies of chromosome 21, causing intellectual disability and characteristic physical features. (Note: most trisomy 21 cases arise from meiotic errors, but mitotic nondisjunction can also produce mosaic forms.)
• Turner syndrome (monosomy X): only one X chromosome in females, leading to short stature and infertility
• Cancer: many solid tumors are aneuploid. Abnormal chromosome numbers can activate oncogenes, inactivate tumor suppressors, and promote drug resistance

The spindle assembly checkpoint (SAC) is the cell's main defense against segregation errors:

• The SAC monitors whether every kinetochore is properly attached to spindle microtubules
• Even a single unattached kinetochore generates a "wait" signal. Proteins like Mad2 and BubR1 assemble at unattached kinetochores and inhibit the anaphase-promoting complex/cyclosome (APC/C), the enzyme complex that would otherwise trigger separase activation and anaphase onset
• Only when all chromosomes achieve bioriented (amphitelic) attachment does the SAC signal shut off, allowing anaphase to proceed

Centrosome amplification is another source of trouble. Cells with more than two centrosomes can form multipolar spindles, which almost always missegregate chromosomes. Cancer cells frequently have extra centrosomes but often survive by clustering them into two functional poles, allowing a roughly bipolar division. This clustering mechanism is itself a potential drug target in cancer therapy.