L3 Genetic regulation of human development and links to cancer

Question 1

Waardenburg Syndrome

Answer 1

Hypopigementation (white forelock, blue eyes) and sensorineural deafness

Question 2

Melanoma

Answer 2

deadly form of skin cancer, likely to metastasise throughout your body

Question 3

Linking development, model organisms and cancer

Answer 3

see one note

Question 4

From fertilisation to 4 cell stage

Answer 4

see onenote

Hasn’t gone through the second stage of meiosis, waiting for the sperm to come

Sperm has to burrow through outer layer of the egg

After pro-nuclei from mother and father fuse => cell undergoes first division

In early division, there is no growth cycle (G1,G2), just division

Question 5

From morula to blastocyst

Answer 5

see onenote

Compaction occurs => leads to fluid filled cavity

Inner cell mass - gives rise to the embryo

Hatches out of the wall of the constraint (zona pellucida) => burrows into the uterus

Question 6

From blastocyst to week 4 embryo

Answer 6

see onenote

Gastrulation - structure of embryo becomes more complex => tissue layers: exoderm, endoderm, mesoderm

Mesodermal cells - cells lose epithelial connection to each other and are able to migrate

Neural plate forms

Question 7

Key concepts of Developmental Genetics

Answer 7

1. cell lineages
2. differentiation and determination
3. differential gene expression
4. pattern formation
5. morphogenesis

Question 8

Cell lineages

Answer 8

see onenote

Genetic equivalence: the original cell (i.e. the zygote) divides into many cells with each cell receiving a full copy of the genome

Cleavage:
early rounds of cell division divide cytoplasm into smaller parts - no growth phase in cell cycle

later cell divisions have G1 and G2 phase so cells maintain size as they proliferate => embryo gets bigger

Question 9

Development can be seen as a cell lineage tree

Answer 9

see onenote

Question 10

Differentiation

Answer 10

see onenote

Differentiate by expressing different genes

cells begin specialise in terms of appearance, behaviour, internal structure, function

Question 11

Differential gene expression

Answer 11

housekeeping genes expressed in all cells

other genes specific to particular types of cells

Question 12

Determination

Answer 12

see onenote

cell’s fate can become determined before one can see outward differences

determined = one could move the cell to a new part of the embryo and it will still differentiate as it would have in its original position

Question 13

Making two cells express different genes

Answer 13

see onenote

symmetric vs asymmetric division

internal vs external signals

Question 14

Stem cells and asymmetric divisions

Answer 14

see onenote

neuroblasts vs ganglion mother cells

Question 15

Asymmetric divisions and cell fate determinants

Answer 15

see onenote

how are different cell fates of NB and GMC achieved?
= segregation of TF prospero to GMC

prospero inhibits self-renewal genes and promotes neural differentiation genes

Question 16

Can label all progeny of neuroblast

Answer 16

see onenote

labelling a single NB with a membrane dye

Question 17

What if there was no Prospero?

Answer 17

see onenote

No prospero - doesn’t produce GMCs => no neurons produced, just more neural stem cells

Question 18

Cell differences achieved by external signals

Answer 18

see onenote

Question 19

General paradigm of signalling pathways

Answer 19

see onenote diagram

1. ligand binds to receptors which induces some change in receptor e.g. conformation
2. this triggers sequence of intracellular events which eventually leads to TF entering nucleus and regulating gene expression

Question 20

Pattern formation

Answer 20

see onenote diagrams

Gene expression is under spatiotemporal control: a process called pattern formation

achieved by complex mix of cell-cell signalling and genetic regulatory networks acting within a cell

Question 21

Morphogenesis

Answer 21

see onenote

Morphogenesis - the genesis of form

achieved by a range of cellular behaviours/mechanisms e.g. division, apoptosis, migration, shape change etc.

Question 22

Morphogenetic mechanisms - Birth and death of cells

Answer 22

see onenote slides

1. cleavage
2. growth
3. apoptosis e.g. vertebrate limb bud development
4. cells can change shape e.g. dendrite
5. mesenchymal to epithelial transition (MET)
6. epithelial to mesenchymal transition (EMT)

Question 23

Collective cell behaviour

Answer 23

see onenote slides

Epithelial folding
- large scale morphogenetic mechanism caused by several epithelial cells changing shapes at once

convergent extention

• field of cells rearrange to change overall shape of tissue
• cells converge along one axis which has the effect of extending the tissue along the other axis

epithelial branching

• epithelial cells can become semi-motile and extend into surrounding mesenchyme in response to growth signals
• occurs during lung formation

Question 24

TF and signalling pathways coordinately regulate many genes at once

Answer 24

see onenote slides

e.g. twist controls many other genes => collectively control the future behaviour of the cell

signalling pathways will typically control many downstream target genes

Question 25

How can we study gene function in development?

Answer 25

see onenote slides

1. expression analysis
2. functional (mutant) analysis

Question 26

Achondroplasia

Answer 26

Dwarfism
- more than 99% of cases caused by mutation to the FGFR3 gene; glycine at position 380 replaced with arginine. Activates the receptor which leads to cartilage precursor cells to stop dividing so bones fail to grow

Question 27

Popular model organisms

Answer 27

worm, Drosophila melanogaster, zebra fish, clawed frog, chick, mouse

Question 28

Tradeoff between utility and relevance

Answer 28

Utility - power as genetic model system e.g. simple genome, quick life cycle

Relevancy - similarity to humans

Question 29

Why use the current model organisms?

Answer 29

see onenote

Worms - complete cell lineage determined

Zebrafish - clear embryo

Chick - classic embryological system e.g. neural studies

Question 30

Cancer

Answer 30

see onenote

is caused by reactivation of genetic programs of development

Cancer uses normal proliferative pathway but is unregulated