What is the role of microtubules in cell division, particularly in mitosis?

Microtubules in Cell Division: Essential Structural and Functional Components

Microtubules form the core structural framework of the mitotic spindle apparatus, which is absolutely critical for chromosome capture, alignment, and segregation during cell division, with their intrinsic dynamic behavior—regulated by microtubule-associated proteins—enabling the mechanical work necessary for faithful transmission of genetic information. 1

Primary Functions During Mitosis

Microtubules execute several indispensable roles throughout the mitotic process:

• Chromosome capture and movement: Microtubules emanating from spindle poles attach to kinetochores on chromosomes, physically capturing them and generating forces for movement 1, 2

• Chromosome congression: Once captured, microtubules facilitate the alignment of chromosomes at the metaphase plate through coordinated polymerization and depolymerization dynamics 1

• Sister chromatid segregation: During anaphase, microtubule dynamics drive the separation of sister chromatids to opposite poles of the dividing cell 1, 2

• Cytokinesis support: Beyond chromosome segregation, microtubules are required for successful completion of cytokinesis, the physical division of the cell 1

The Mitotic Spindle Apparatus

The mitotic spindle is a macromolecular structure primarily comprised of microtubules that must assemble with precise spatial and temporal coordination 3. The spindle apparatus demonstrates remarkable scaling capacity, adapting its length and mass to cell size—particularly evident during early embryo cleavage when cells divide rapidly without growth, reducing volume at each division. 3

• Spindle assembly occurs within a relatively short, constant time window that remains independent of cell size across many species 3

• The spindle can sense cellular dimensions and scale appropriately over an order of magnitude in early embryos 3

Regulation by Microtubule-Associated Proteins

The functional capacity of microtubules during mitosis depends entirely on regulation by microtubule-associated proteins (MAPs), which can be classified into distinct functional categories 1:

1. Stabilization proteins: Promote and stabilize microtubule polymerization 1

2. Destabilization proteins: Induce depolymerization or severance of microtubules 1

3. Linker proteins: Connect microtubules to chromosomes, centrosomes, and other cellular structures 1

4. Motor proteins: Generate force and movement along microtubule tracks 1

End-Binding Protein Networks

End-binding proteins (EBs) form critical nodes in microtubule plus-end interaction networks 4. In budding yeast, the EB protein Bim1 executes its key mitotic functions as part of two distinct cargo complexes: Bim1-Kar9 in the cytoplasm and Bim1-Bik1-Cik1-Kar3 in the nucleus, with the latter supporting initial metaphase spindle assembly, tension establishment, and sister chromatid biorientation. 4

Dynamic Instability: The Key to Microtubule Function

Microtubules possess intrinsic dynamic behavior—alternating between phases of growth and shrinkage—which is the fundamental property enabling them to perform mechanical work during mitosis. 1 Without proper regulation of these dynamics by MAPs, microtubules could not accomplish chromosome segregation or any other mitotic task 1.

• During mitosis, microtubules are highly dynamic, contrasting with their relative stability in non-dividing cells such as neurons where they support axon extension 2

• Different physical properties (stability versus dynamics) correlate with different cellular functions 2

Clinical Relevance: Microtubules as Therapeutic Targets

Microtubules represent a well-established target in cancer chemotherapy because disruption of microtubule dynamics through stabilization or destabilization results in mitotic arrest and apoptotic cell death. 5

• Anti-microtubule agents bind at three primary sites: the vinblastine site, taxol site, or colchicine site 5

• Colchicine binds at the interface of tubulin heterodimers and induces microtubule depolymerization 5

• The principle underlying microtubule-targeted drugs is to arrest cells at mitosis and reduce their growth, exploiting cancer's characteristic of unchecked cell proliferation. 5

Important Caveat on Colchicine

While colchicine and colchicine-binding site inhibitors have been extensively studied, their use in cancer treatment is limited by dose-limiting toxicity and resistance in humans 5. Combination therapy represents a potential strategy to overcome these limitations 5.

Mitotic Catastrophe and Microtubule Dysfunction

Perturbations of the mitotic apparatus—including chromosomes and the microtubule complex—initiate mitotic catastrophe, an oncosuppressive mechanism that can lead to cell death or senescence rather than constituting a pure cell death pathway itself. 6

• Aberrant mitosis frequently produces gross nuclear alterations including micro- and multinucleation 6

• Time-lapse fluorescence microscopy or high-throughput video microscopy is necessary to properly assess mitotic catastrophe, as end-point techniques cannot reconstruct the sequence of events leading to cell death 6