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Control Cell Growth
Organisation of the Body
| Question | Answer |
|---|---|
| Possible paths for undifferentiated cells | Differentiate (enter G0) Apoptosis - a cell can die Proliferated - mitotic division Grow Proliferation and growth are coupled to produced cells all of a uniform size |
| Cell growth | The major determinant of organ and body size - to get bigger there must be cell growth Its effects can be countered by cell death - apoptosis or necrosis |
| What does cell growth require | Increase in cell mass and volume - macromolecular synthesis Relative movement at cell surface - change in contact with surrounding cells Change in cell volume and shape - e.g. neurons sending out an axon |
| Why is organ size/cell growth regulation important | Massive but consistent size increase during development Remarkable differences in animal size but with similar processes Organs are maintained in proportion to each other Cells in many organs continue to grow in adults but do not change size |
| Key ideas in growth regulation | Cells grow at all stages of life Cell growth and proliferation are normally coupled Cell growth is influenced by extracellular growth factors and inhibitors Organs grow to a fixed size in normal conditions Growth can be modulated by extrinsic factors |
| Cell growth in adults | Hypertrophy (growth) e.g. skeletal muscle cells increase in size. Hyperplasia (coupled growth and proliferation) in renewing tissues e.g. stem cells (constantly dividing) as well as resting tissues e.g. liver regeneration (self limiting and reversible) |
| Cell growth in disease | Seen abnormally in neoplasia - tumour growth Often when stem cells loose control and divide abnormally |
| Cell growth in normal development | Fertilised egg >> embryo >> fetus >> adult >10^9 fold increase in size |
| When does cell loss take place | In development - tissue patterning e.g. digit formation Limb buds grow out with cell death between digits forming final structures In neural patterning - e.g. retinal ganglion cells and NGF Many neurons have to be lost for nervous system to function |
| When does Hypoplasia occur | In development - tissue patterning and neural patterning Physiological atrophy - ductus arteriosus at birthe (loss of blood vessel from fetus) or thymus at puberty |
| Hypoplasia in disorders | Hypoplasia and atrophy e.g. testes in Klinefelter's syndrome (testes have abnormal support so they atrophy and degenerate (XXY) Skeletal muscle degeneration after denervation Neurodegenerative diseases of aging |
| How to study cell growth | Analysis in cultured cells Experimental manipulation of organs/tissues in whole animals Genetic analysis in whole animals (modulate genes and see if they play a role) e.g. humans, mice, yeast and fruit flies (cell growth is highly conserved) |
| The cell cycle and growth | As cells grow they produce cyclins faster. These control restriction points in the cell cycle, driving cells through the cycle to division. Increased G1/S and G2 cyclin dependant kinases due to growth drive cells to proliferate faster. |
| Relationships between growth and proliferation | Growth = proliferation Proliferation does not equal growth Growth drives the cell cycle by regulating restriction points, therefore faster growth = faster division (more cyclins formed) |
| Evidence from flies for how growth drives the cell cycle | Bind cells to GFP to visualise Add E2F(drives cell cycle)more cells in the same volume Add Rb(slow cell division)less cells same volume Add growth factor signalling gives more cells in larger volume. Growth is needed to drive proliferation |
| When do growth and proliferation uncouple | Proliferation but no growth e.g. cleavage (seen in early embryo) Growth but no proliferation e.g. skeletal muscle hypertrophy Growth, DNA replication but no cell division e.g. 4N myocardial cells, N.B. ploidy in salamanders (2n or 4n) gives larger cells |
| What molecules control growth | Growth inhibitors - less well characterised e.g. myostatin (TGF-beta homologue) Growth factors - since growth usually drives proliferation these molecules typically act as mitogens too. (drives cell cycle) |
| Evidence for growth inhibitors | Mice with myostatin deficiency have larger skeletal muscle (up to 3 fold mass increase) Belgian Blue Bull has a mutation in the myostatin gene so have high levels of skeletal muscle. Inhibitors of myostatin are used by athletes to increase muscle mass. |
| Investigating eukaryotic primary cell structure | Normal tissue explant is placed in a petri dish in a medium of amino acids, balanced salts, a bicarbonate buffer, 5% CO2 in gas phase and 50% calf serum. This mixture is minced and digested with trypsin to form single/clumped cells. (a monolayer of cells) |
| Primary to secondary cell structure | Primary culture (mixed types of diploid cells mainly fibroblasts) is trypsinised and subcultured many times to form the secondary structure of pure fibroblasts which have a lifespan of 50 doublings. Reguires contact with a self produced ECM and serum |
| What is serum | Growth factors are a key component of serum. These are required by the fibroblasts in culture to continue growing |
| How do growth factors work | Binds to a dimerised GF receptor. This activates an intracellular signalling cascade as a positive feedback loop. This can directly increase macromolecular synthesis or many activate transcription factors that activate target genes, having the same effect |
| Examples of Growth factors | Fibroblast growth factor Insulin-like growth factor Nerve growth factor Epidermal growth factor Transforming growth factor (alpha/beta) |
| Types of growth factor | Global with global effects - effects all structures e.g. growth hormone acts via endocrine system Global with specific effects - e.g. erythropoietin produced in kidney affects erythrocyte precursors in bone marrow Local with local effects - e.g. NGF |
| Difference between local and global factors | Local factors often control growth of specific organs, global factors can regulate co-ordinated growth (e.g. nutrient dependant) of multiple organs |
| Transplantation experiments to determine how organ size is regulated | Usually organs determine size autonomously e.g. transplant multiple fetal thymuses into developing mouse - each grows to adult size But transplant fetal spleens and total mass of spleens = mass of normal spleen. This is non-autonomous control |
| Regeneration experiments to determine how organ size is regulated | Hepatocytes can regenerate 2/3 of liver provided a circulatory system is present. Uses Vascular endothelial GF. Liver autonomously returns to normal size |
| Non-autonomous control of organ size | Defects in regulatory pathways - e.g. growth hormone IGF1 reduced with excess GH forms small or larger organs. Insulin receptor mutant - leprechaunism in humans (Donohue syndrome) This is under endocrine control and is linked to nutrition |
| Insulin receptor signalling and cell growth | In flies increased InR signalling produces large flies while reduced InR signalling produces small flies. This is based on global nutrition regulation and growth signals Mice deficient in growth hormone and IGF1 have proportional organs but remain small |
| Variation in IGF1 and dog size | Small dogs all have one allele of IGF1 whilst big dogs do not have the allele. This suggests that this mutation dictates the amount of IGF1 expressed, therefore affecting growth |
| Effect of nutrition on health | When mothers do not have normal nutrition in pregnancy, babies have a low birth weight and tend to have shorter lifespans. This suggests that epigenetic factors can also effect expression of growth hormones and level of growth control can effect lifespan |
| Role of signals from other structures in growth (neurotrophic signals) | NGF controls size of sympathetic neurons NGF controls survival of retinal ganglion cells Retinal ganglion cells project into the brain, with those receiving signals from NGF surviving. Ones who don't receive signals die |
| Growth and patterning | To construct an organ growth has to be coordinated with patterning - organ has to look right e.g. aspects in correct location Expression of growth factors is important |
| Role of FGF7 in growth | Fibroblast GF7 in dermis stimulates growth and proliferation of epidermal basal cell layer proliferation above the dermis in wound healing (increases expression when skin damaged) |
| Role of FGF8 and FGF4 in growth | Stimulate growth and proliferation in underlying mesenchyme in apical ectodermal ridge of chock limb bud. Expressed genes in the surface of epidermis diffuse down into the underlying structure to stimulate growth and form a limb bud |
| What is one growth regulated by (IGF1 and FGF) | IGF1 from local chondrocytes stimulated by GH Fibroblast growth factors instruct cells to differentiate into cartilage not divide (dominant mutation in FGF receptor linked to achondroplasia) |
| What is bone growth regulated by (Steroids and Thyroid/parathyroid related hormone) | Steroids e.g. oestrogen/testosterone regulating prepubertal growth and subsequent cessation of growth (males lacking oestrogen receptor keep growing) Thyroid/parathyroid related hormone controls hypertrophy and maturation |
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