L8 - Biology of Stem Cells, Ageing and Cancer Flashcards by Ellie R

What are the two different types of ageing?

Not only related to old age

Post-embryonic development – growth

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What is patterning?

Patterning - small scale followed by growth

Cell patterning events, e.g. action of morphogens, function over a limited range

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The final shape and size of an organism is determined by?

Growth

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Growth can occur in which 3 ways?

Proliferation
Cell enlargement
- Cardiac hypertrophy
- Skeletal muscle
Accretion
- Bone
- ECM is laid down outside the cell

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What are the 5 phases of the cell cycle?

G1 - cell enlarges
S - DNA is replicated 
G2 - together G1, S and G2 phase = interphase
M - cell divides
G0 – resting phase

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What is the cell cycle driven by?

Cyclins which activate CDKs
These in turn control proteins that trigger events of each phase
Cyclins fluctuate in concentration

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At what stage of the cell cycle are fully differentiated cells found?

Usually in G0 and do not proliferate

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How is cell division in Drosophila intrinsically controlled?

Drosophila initially develops as a syncytium – single cell with multiple nuclei

Nuclei go through rapid synchronous cell cycles - only S and M phases
At 14th cycle the cycle slows and G2 phase introduced
Nuclei migrate to periphery and get surrounded by involuting cell membrane - cellularization
Depending on its precise position, each cell will acquire its own cell division rate
- Groups of cells with similar fates will show similar division cycles - mitotic domains
Cell division in these domains is controlled by a protein – String

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What is string?

Phosphatase that activates CDKs
During first 13 divisions uniformly distributed maternally-supplied string
After 13th division zygotically expressed string produced under control of patterning genes

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Why is mesoderm one of the first domains to express string but 10th domain to divide?

Due to a protein call tribble - an inhibitor of string

Tribble is induced by mesoderm inducing genes
Functions to promote invagination by preventing cell division at inappropriate times

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What are mitotic domains controlled by?

String expression
PO4-ase
Activate CDKs

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What is string controlled by?

Patterning genes - Gap, Pair rule, segment polarity

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What does control of growth depend on?

The organ

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What is the difference between thymus intrinsic and spleen systemic?

Thymus intrinsic
- If additional thymus glands are transplanted all organs maintain their size
- Multiple amounts of tissue will be present
Spleen systemic
- If additional spleens are transplanted both spleens will only grow to half the size
- Total amount of tissue remains the same

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In animals what is growth dependent on?

Absolute dimensions, not cell number is important
Ploidy affects cell size but not overall size of an animal
Dependent on morphogens, not growth factors –> steepness of morphogen gradients

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What happens if limb bud is transplanted between two species of newt embryos

Intrinsic growth characteristics maintained

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What are the two growth control pathways?

TOR pathway –> cell size growth

Hippo pathway –> limit organ size

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What happens when the Hippo pathway is inactive?

Yki/Yap/Taz in the nucleus stimulating growth and survival of cells
Various factors lead to inactivation – mechanical stress, other signalling pathways

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What happens when the Hippo pathway is active?

Yki/Yap/Taz excluded from nucleus

Various factors lead to activation - cell cell contact, cell polarization

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What happens in a hippo mutant?

lLst growth restriction – Yki in nucleus

What is the size of different parts of the body controlled by?

Controlled by rate and duration of growth - declining rate then second spurt

Examples of the two stage growth in humans and pygmies

Both boys and girls grow rapidly initially, growth rate then drops until puberty sets in
In pygmies second growth phase does not occur – explains their short stature

How is the size of the Drosophila controlled?

Size of adult determined by size of larva
Insulin affects duration and rate of larval growth
- Insulin deficient flies remain smaller – smaller cells and fewer of them
Edcyson induces metamorphosis

Genome analysis in dogs have identified which pathways as main determinants of size differences between breeds?

The IGF and GH pathways

Human and dog loci linked to the IGF and GH pathways?

In human GWAS studies many more loci have been identified but most have only minor effects The few loci identified in dogs breeds, may be the result of strong selection by humans of rare variants

In humans which hormones control growth pattern?

Insulin-like growth factors 1/2 | Growth hormone

What sort of growth does growth hormone control?

Post embryonic

What is growth hormone production stimulated by?

Growth hormone releasing hormone

What is growth hormone inhibited by?

Somatostatin

Many of growth hormones effects are mediated via?

Insulin-like growth factors

How does growth hormone feed back on its own production?

Promotes somatostatin and inhibits growth hormone releasing hormone

How was it shown that the maternal environment effects fetus development in the womb?

Followed babies exposed to famine early mid and late gestation - Early exposure - Weight and size compensated - Increased risk for obesity, diabetes, CHD

What is the difference between a foal of a shire and Shetland if the mother is either breed?

A Shetland - foal is smaller A Shire - foal is larger However both will grow to the same size

How was it shown that in humans inadequate growth in utero can lead to lifelong consequences?

Short period of severe food deprivation in the Netherlands

How do some animals not directly develop into an adult form?

Many insects develop a larval form - adult structures hidden as imaginal discs

What is the difference between the signals involved in early and post-embryonic development?

Signals involved in development - Short range and small size Signals involved in post embryonic development (molting and metamorphis) - Influences from environment act on the CNS - CNS in turn produces hormones

How do arthopods grow?

The cuticle of arthropods is rigid and does not allow growth - larvae of insects have to molt to grow

What is the molting process known as?

Ecdysis

Molting method

1. Intermold stages are called instars 2. Initiated by activation of stretch receptors in the cuticle 3. Leads to release of protothoracicotropic hormone from corpus alatum 4. Leads to release of ecdyson from the protothoracic gland

How is metamorphis controlled in tadpoles?

Change in the balance of prolactin and thyroxine causes metamorphosis

How is metamorphis controlled in insects?

1. Nutrition, temperature and light 2. Act via the hypothalamus affecting the levels of juvenile hormone and ecdysone - Juvenile hormone prevents metamorphosis - Ecdysone promotes metamorphis 3. Secretion of corticotropin releasing hormone which acts on pituitary cells 4. Secretion of thyroid stimulating hormone which acts on the thyroid 5. Secretion of thyroxin 6. Positively feeds back on itself - if certain levels reached metamorphosis becomes irreversible - Causes growth of the limbs but degeneration of the tail - Modulates responsiveness to other signals e.g. estrogen

In what tissues is cancer most common in?

In tissues that continue to divide throughout life | - Cell division can lead to copying errors

Where do most cancers occur?

Epithelia and blood 85% of cancers occur in epithelia Failure in normal differentiation process that occurs during development or maintenance Usually mutations acquired - teratoma

Teratoma cancer cell characteristics

Teratoma cancer cells can give rise to tissues from all three germ layers In mice - murine teratoma cells transplanted to embryos and can participate normally in the formation of the animal - Not permanently transformed

What are proto oncogenes?

After activation become oncogene --> cancer | Ras, Raf, Epidermal Growth Factor Receptor, Myc

What are tumour suppressor genes?

After inactivation --> cancer | Retinoblastoma, p53, Ptc, adenomatous polyposis coli, Von Hippel Lindau

How can developmental signals cause cancer?

Negative regulators of developmental signal transduction pathways - Ptc regulating Hh - APC regulating Wnt These pathways also play a role in stem cell renewal

Examples of aberrant development signals that drive cancer

Activated Wnt - colon cancer, hepatocellular cancer Activated Hh - basal cell carcinoma, medulloblastoma Activated Nodal - melanoma Activated Notch - leukemia Activated EGF - lung cancer, breast cancer BRCA1, BRCA2, P53 - Mutations in tumor suppressors or oncogenes that lead to genome instability - Resulting mutations may lead to aberrant developmental signals

Which type of gene is the basis of a class of dominant hereditary diseases?

Tumour suppressor genes Patients inherit one defective copy of the gene Will lead to excessive cell proliferation and can ultimately result in cancer