Cell Cycle, Mitosis and Differentiation (AAMC 2C)
A fertilized egg becomes a body of trillions of specialized cells through three linked processes: controlled division, programmed death and differentiation. This page covers the cell cycle and its checkpoints, the stages of mitosis, what goes wrong in cancer, how apoptosis removes cells cleanly, how stem cells commit to a fate, and the first weeks of embryonic development. MCAT passages often hand you an experiment (a drug that blocks a phase, a knocked-out checkpoint gene, a transplanted tissue) and ask you to predict the result.
Phases of the Cell Cycle
The eukaryotic cell cycle has two big parts: interphase, where the cell grows and copies its DNA, and the M phase (mitosis plus cytokinesis), where it divides. In a typical rapidly dividing human cell, interphase takes roughly 90% of the cycle.
| Phase | What happens | DNA content (diploid human cell) |
|---|---|---|
| G1 (gap 1) | Growth, protein and organelle synthesis; the cell "decides" whether to divide | 46 chromosomes, 46 chromatids (2n, 2c) |
| G0 | Non-dividing resting state; mature neurons and most muscle cells stay here | 2n, 2c |
| S (synthesis) | DNA replication; centrosome duplication begins | Rises from 2c to 4c |
| G2 (gap 2) | More growth; checks that replication is complete and correct | 46 chromosomes, 92 chromatids (2n, 4c) |
| M | Mitosis (nuclear division) and cytokinesis (cytoplasmic division) | Ends as two cells at 2n, 2c |
Mitosis
Mitosis produces two genetically identical diploid daughter cells. It is used for growth, tissue repair and asexual reproduction.
- Prophase: chromatin condenses into visible chromosomes; the mitotic spindle forms as centrosomes move apart; the nucleolus disappears.
- Prometaphase: the nuclear envelope breaks down; kinetochores (protein complexes on each centromere) capture spindle microtubules.
- Metaphase: chromosomes line up single-file at the metaphase plate, with sister kinetochores attached to opposite poles. This is the best stage for a karyotype.
- Anaphase: the enzyme separase cleaves cohesin, sister chromatids separate, and kinetochore microtubules shorten to pull them to opposite poles while polar microtubules push the poles apart.
- Telophase: nuclear envelopes re-form, chromosomes decondense, and nucleoli reappear.
- Cytokinesis: in animal cells an actin-myosin contractile ring pinches the cell to form a cleavage furrow; plant cells build a cell plate from Golgi vesicles.
Mitosis vs meiosis in one table
| Feature | Mitosis | Meiosis |
|---|---|---|
| Divisions | One | Two (meiosis I and II) |
| Products | 2 identical diploid cells | 4 genetically different haploid cells |
| Homologous pairing (synapsis) | No | Yes, in prophase I, with crossing over |
| What separates in anaphase | Sister chromatids | Homologs (anaphase I), then sister chromatids (anaphase II) |
| Where | Somatic cells | Germ cells in gonads |
Cell Cycle Control and Checkpoints
Progress through the cycle is driven by cyclin-dependent kinases (CDKs). CDK levels stay fairly constant, but a CDK is only active when bound to its partner cyclin, and cyclin levels rise and fall each cycle as they are made and then destroyed by ubiquitin-mediated proteolysis. Active cyclin-CDK complexes phosphorylate target proteins that push the cell into the next phase.
The main commitment step. Growth factors raise cyclin D, which activates CDK4/6. These phosphorylate Rb (retinoblastoma protein), releasing the transcription factor E2F, which switches on S-phase genes. If DNA is damaged, p53 accumulates and induces p21, a CDK inhibitor, to halt the cycle so repair can happen; if the damage is too severe, p53 triggers apoptosis.
Checks that DNA replication is complete and undamaged before mitosis. Cyclin B with CDK1 forms MPF (maturation or M-phase promoting factor), which drives entry into mitosis.
Anaphase is held back until every kinetochore is properly attached to the spindle. Once all are attached, the anaphase-promoting complex (APC/C) tags securin and cyclin B for destruction, which frees separase to cut cohesin. Failure of this checkpoint can cause nondisjunction and aneuploidy.
Cancer
Cancer is uncontrolled cell division caused by accumulated mutations, usually in genes that regulate the cell cycle, DNA repair or apoptosis. Most cancers need several hits over time, which is why incidence rises with age.
| Feature | Proto-oncogene → oncogene | Tumor suppressor gene |
|---|---|---|
| Normal role | Promotes division (growth factors, receptors, Ras, Myc) | Restrains division or triggers repair and apoptosis (p53, Rb, BRCA1/2, APC) |
| Cancer mutation | Gain of function | Loss of function |
| Alleles needed | One mutant allele is enough (dominant at the cell level) | Usually both alleles must be lost ("two-hit" model; recessive at the cell level) |
| Analogy | Stuck accelerator | Broken brakes |
Features of cancer cells
- Divide without growth signals and ignore anti-growth signals.
- Lose contact inhibition and anchorage dependence, so they pile up in culture.
- Evade apoptosis and often reactivate telomerase, giving unlimited replication.
- Induce angiogenesis (new blood vessels) to feed the tumor.
- Malignant tumors invade nearby tissue and metastasize through blood or lymph; benign tumors stay localized.
Carcinogens act by damaging DNA (chemicals, UV, ionizing radiation) or by viral oncogenes such as HPV proteins that inactivate p53 and Rb.
Apoptosis
Apoptosis is programmed, orderly cell death. It sculpts the embryo (for example, removing the webbing between fingers), deletes self-reactive lymphocytes, and removes damaged or infected cells.
- Intrinsic (mitochondrial) pathway: internal stress such as DNA damage tips the balance of the Bcl-2 family toward pro-apoptotic members (Bax, Bak). The outer mitochondrial membrane becomes permeable, cytochrome c leaks into the cytosol, and it forms the apoptosome that activates initiator caspase-9.
- Extrinsic (death receptor) pathway: a ligand such as Fas ligand or TNF binds a death receptor and activates initiator caspase-8.
- Both converge on executioner caspases (such as caspase-3), proteases that dismantle the cell.
| Feature | Apoptosis | Necrosis |
|---|---|---|
| Trigger | Regulated, often physiological | Injury: ischemia, toxins, trauma |
| Cell size | Shrinks | Swells |
| Membrane | Intact; buds into apoptotic bodies | Ruptures; contents leak out |
| Inflammation | None; phagocytes clear the bodies | Yes |
| Energy | Requires ATP | Passive |
Stem Cells and Differentiation
A stem cell can self-renew and produce specialized descendants. Potency describes how many cell types it can become:
- Totipotent: every cell type including extraembryonic tissues (placenta). The zygote and the earliest blastomeres.
- Pluripotent: any cell of the three germ layers, but not a whole organism. Embryonic stem cells from the inner cell mass, and induced pluripotent stem cells (iPSCs) made by reprogramming adult cells with a few transcription factors.
- Multipotent: several types within one lineage. Hematopoietic stem cells make all blood cells; mesenchymal stem cells make bone, cartilage and fat.
- Unipotent: one cell type, such as some epidermal or muscle satellite cells.
How cells commit
Determination is the irreversible commitment to a fate, which can happen before any visible change. Differentiation is the later expression of the specialized genes and structures. Every somatic cell carries the same genome; differentiation is a matter of selective gene expression, set by transcription factors and epigenetic marks.
Signals that shape fate:
- Cytoplasmic determinants: molecules unevenly distributed in the egg, so daughter cells inherit different instructions (asymmetric division).
- Induction: one group of cells changes the fate of a neighboring group, for example the notochord inducing overlying ectoderm to form the neural plate.
- Morphogens: secreted signals that form a concentration gradient; cells read the local concentration to set position and identity.
- Homeobox (Hox) genes: transcription factors that specify body segments along the head-to-tail axis; mutations can put the right structure in the wrong place.
Embryogenesis Basics
- Fertilization usually occurs in the ampulla of the uterine tube and forms a diploid zygote. The cortical reaction blocks polyspermy.
- Cleavage: rapid mitotic divisions without growth, so cells get smaller while the embryo stays the same size. A solid ball of cells is a morula.
- Blastulation: a fluid-filled cavity forms, giving the blastocyst: an outer trophoblast (becomes the chorion and fetal part of the placenta) and an inner cell mass (becomes the embryo). The blastocyst implants in the endometrium about a week after fertilization.
- Gastrulation: cells migrate inward to form three germ layers.
- Neurulation: the notochord induces ectoderm to form the neural plate, which folds into the neural tube (brain and spinal cord). Neural crest cells leave the folds and migrate widely.
| Germ layer | Main derivatives |
|---|---|
| Ectoderm | Epidermis, hair, nails, nervous system, lens of the eye, adrenal medulla and other neural crest derivatives |
| Mesoderm | Muscle, bone and connective tissue, heart and blood vessels, blood, kidneys, gonads, adrenal cortex |
| Endoderm | Epithelial lining of the digestive and respiratory tracts, liver, pancreas, thyroid, bladder lining |
Aging and regeneration
Most somatic cells can divide a limited number of times (the Hayflick limit) because telomeres shorten. Tissues differ in regenerative capacity: liver and epithelium regenerate readily, cardiac muscle and most neurons do not. Senescent cells stop dividing but remain metabolically active.
Worked MCQs
Five MCQs on the patterns the exam returns to most often. Read every explanation, including the ones you got right.
Q1. A human somatic cell has 46 chromosomes in G1. How many chromatids does it contain at metaphase of mitosis?
DNA is replicated in S phase, so each of the 46 chromosomes has two sister chromatids by metaphase: 46 × 2 = 92 chromatids. The chromosome count is still 46 because the sisters share a centromere until anaphase.
Q2. Which statement best describes a mutation that turns a proto-oncogene into an oncogene?
Proto-oncogenes promote growth, so an activating (gain-of-function) mutation in a single allele can drive division. Loss of function in both alleles describes tumor suppressors such as p53 and Rb. Increased caspase activity would cause more apoptosis, not cancer.
Q3. Which structure is derived mainly from embryonic mesoderm?
Mesoderm forms muscle, bone, connective tissue, the cardiovascular system, blood and kidneys. The epidermis and neural tube come from ectoderm, and the gut lining comes from endoderm.
Q4. Which observation is most characteristic of apoptosis rather than necrosis?
Apoptosis is an ordered, ATP-dependent process: the cell shrinks, its chromatin condenses, and it breaks into apoptotic bodies that phagocytes remove quietly. Swelling, rupture, leakage and inflammation are signs of necrosis.
Q5. A cell has one chromosome whose kinetochores are not attached to spindle microtubules. Where in the cycle will the cell most likely pause?
The spindle assembly checkpoint keeps the anaphase-promoting complex inactive until every kinetochore is attached. Until then separase stays inhibited, cohesin is not cut, and the cell waits in metaphase. This protects against nondisjunction.
Quick Recap
- Interphase (G1, S, G2) then M phase; G0 is the non-dividing exit.
- Mitosis: prophase, prometaphase, metaphase, anaphase, telophase, then cytokinesis; result is 2 identical diploid cells.
- Cyclins rise and fall; CDKs are active only with cyclin. p53 → p21 halts G1; Rb holds E2F until phosphorylated.
- Spindle checkpoint: APC/C waits until all kinetochores attach, then separase cuts cohesin.
- Oncogenes: gain of function, one allele. Tumor suppressors: loss of function, usually both alleles.
- Apoptosis: caspases, cytochrome c, shrinkage, no inflammation. Necrosis: swelling, rupture, inflammation.
- Potency: totipotent > pluripotent > multipotent > unipotent. Differentiation is selective gene expression.
- Zygote → morula → blastocyst → gastrula (3 germ layers) → neurula.