L3 Genetic regulation of human development and links to cancer Flashcards
Waardenburg Syndrome
Hypopigementation (white forelock, blue eyes) and sensorineural deafness
Melanoma
deadly form of skin cancer, likely to metastasise throughout your body
Linking development, model organisms and cancer
see one note
From fertilisation to 4 cell stage
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
From morula to blastocyst
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
From blastocyst to week 4 embryo
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
Key concepts of Developmental Genetics
- cell lineages
- differentiation and determination
- differential gene expression
- pattern formation
- morphogenesis
Cell lineages
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
Development can be seen as a cell lineage tree
see onenote
Differentiation
see onenote
Differentiate by expressing different genes
cells begin specialise in terms of appearance, behaviour, internal structure, function
Differential gene expression
housekeeping genes expressed in all cells
other genes specific to particular types of cells
Determination
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
Making two cells express different genes
see onenote
symmetric vs asymmetric division
internal vs external signals
Stem cells and asymmetric divisions
see onenote
neuroblasts vs ganglion mother cells
Asymmetric divisions and cell fate determinants
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
Can label all progeny of neuroblast
see onenote
labelling a single NB with a membrane dye
What if there was no Prospero?
see onenote
No prospero - doesn’t produce GMCs => no neurons produced, just more neural stem cells
Cell differences achieved by external signals
see onenote
General paradigm of signalling pathways
see onenote diagram
- ligand binds to receptors which induces some change in receptor e.g. conformation
- this triggers sequence of intracellular events which eventually leads to TF entering nucleus and regulating gene expression
Pattern formation
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
Morphogenesis
see onenote
Morphogenesis - the genesis of form
achieved by a range of cellular behaviours/mechanisms e.g. division, apoptosis, migration, shape change etc.
Morphogenetic mechanisms - Birth and death of cells
see onenote slides
- cleavage
- growth
- apoptosis e.g. vertebrate limb bud development
- cells can change shape e.g. dendrite
- mesenchymal to epithelial transition (MET)
- epithelial to mesenchymal transition (EMT)
Collective cell behaviour
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
TF and signalling pathways coordinately regulate many genes at once
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
How can we study gene function in development?
see onenote slides
- expression analysis
- functional (mutant) analysis
Achondroplasia
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
Popular model organisms
worm, Drosophila melanogaster, zebra fish, clawed frog, chick, mouse
Tradeoff between utility and relevance
Utility - power as genetic model system e.g. simple genome, quick life cycle
Relevancy - similarity to humans
Why use the current model organisms?
see onenote
Worms - complete cell lineage determined
Zebrafish - clear embryo
Chick - classic embryological system e.g. neural studies
Cancer
see onenote
is caused by reactivation of genetic programs of development
Cancer uses normal proliferative pathway but is unregulated
