1st week: 2 Flashcards
What is studied with animal models? (6)
- A gene and its encoded protein (and different isoforms)
- how specific genes and proteins interact
- the signalling pathway and how it works
- the formation/ specification of cell types, tissues and organs
- the circuits and networks in the nervous system
- the above in relation to disease
What are these phyla:
Chordata?
Arthropoda?
CHORDATA: animals in this category have notochords (not always a vertebrate). Frogs etc. also humans
ARTHROPODA: insects
HUMAN:
Kingdom: Animalia
Phylum: Chordata
Class: Mammalia
Order: Primates
Suborder: Haplorhini
Infraorder: Simiiformes
Family: Hominidae
Subfamily: Homininae
Tribe: Hominini
Genus: Homo
Linnaeus, 1758
How far apart in evolution are humans to insects?
500 million years
Why study animals?
Main reason:
understand causes, mechanisms, pathways from molecule to mind
The relative position or connection in homologous parts; they may differ to almost any extent in form and size, and yet remain connected together in the same invariable order.
Darwin, 1876, p. 382
What is this principle?
Homology
Example of what?
Homologous genes/proteins
Sequence identity between orthologous genes/proteins from different species
Methods possible/used in animal studies:
- mutating, inactivating or overexpressing a gene/protein
- finding interacting/ binding partners
- screening for enhancers/ suppressors
of ‘disease gene/protein’ - epistasis tests and manipulation of a signalling pathway
- targeted activation/ inactivation of neural circuits
- the regulation and function of behaviour
What are these?
otd/Otx
unpg/Gbx2
Pax2/5/8
Hox1 orthologs
Genetic similarities between fly and mouse (and human)
Hirth & Reichert 1999
Baker’s yeast has been used to discover …. and their function in the regulation of the cell cycle/cell division.
Baker’s yeast has been used to discover genes and their function in the regulation of the cell cycle/cell division.
baker’s/brewer’s yeast is …cell
eukaryotic cell
What is in the picture?
cell division of bakers yeast
TDP-43and FUS genes has been discovered to be involved in the formation of …. disease.
Explain picture:
Glucose =
Galactose =
TDP-43 and FUS genes has been discovered to be involved in the formation of motor neuron disease.
TDP-43 and FUS inhibit the growth of yeast cultures, they build aggregates = they are toxic.
Glucose = gene has been turned off
Galactose = gene has been turned on
What does FUS, TAF15 and TDB-43 do in yeast?
What is the importance in human disease?
Form aggregates, means they are toxic.
Couthouis et al. (2011)
In human postmortem samples it is visible that human homolog of TAF 15 also forms aggregates in ALS cases, which stands for amyotrophic lateral sclerosis.
Couthouis et al. (2011)
What animal:
simple anatomy
959 somatic nuclei
302 neurons
transparent
small (1mm long)
250 progeny per generation
easily cultivated
eats bacteria
grown on agar plates seeded
with bacteria
rapid development (three days
life cycle at 25°C)
C. elegans
Who got a Nobel Prize for finding out that C. Elegance has 959 cells
John Sulton 2002
C. Elegance:
How many larval stages?
What is dauer?
L1 - L4
a stage where larva can survive for 4 months, doesn’t mature into an adult.
daf-2 and daf-16 define …. in C. elegans
daf-2 and daf-16 affect each other in what way?
daf-2 and daf-16 define lifespan in C. elegans
Kenyon et al. (1993)
High levels of daf-2 causes the suppression of daf-16, which therefore are low, which leads to a normal lifespan, around 25 days.
daf-2 is low, it leads to the derepression of daf-16, which then leads to high levels of this protein, and that extends the lifespan. See image!!
What’s the importance of daf-2, daf-16 and TOXO in humans?
daf-2 /IGF1 is insulin receptor in humans!
(Affects life span)
Gems & Partridge (2013)
What animal?
- 180 Mb sequenced genome, 13,600 genes
(Compared to ~25,000 human genes)
- 65 per cent structural identity to human genes
Complex brain and behaviour, including learning and memory
- molecular, cellular and behavioural studies in vivo
Drosophila melanogaster
What animal was first with fully mapped genome
Fruit fly, drosophila melanogaster
Who studied chromosomes and inheritance using drosophila melanogaster?
When
1912
Thomas Hunt Morgan
Columbia University
Drosophila melanogaster life cycle?
10-12 days
egg - larva - adult
Drosophila transactivation tool, GAL4/UAS system.
Can be used as what?
Example
Enhancer in generating transgenic flies.
For example, as an enhancer that is specific for all the dopaminergic neurons.
When all the dopaminergic neurons are active, enhancer is transcriptionally active. It recognises the abstract activating sequence of a second set. That could for example be a green fluorescent protein.
Muqit & Feany (2002)
What neuron circuit is studied in Drosophila melanogaster by Dr. Hirth?
Involved in what human activity?
Dopaminergic pathway
Voluntary movement.
Hirth (2010); Strausfeld & Hirth (2013)
Genetic strings:
- forward genetics?
- reverse genetics?
Forward genetics:
Starting with a mutant phenotype, then identify the protein and the gene (Thomas Hunt Morgan)
Reverse genetics:
Knowing the (human) gene, then going to Drosophila, looked whether it has a human homolog, or a fly homolog in this case, and then we started to manipulate that gene, and then, we could look, how does that relate to the disease.
(picture on the slide wrong?)
Behavioural phenotype caused by disease-related genes/proteins can be tested with Drosophila.
Give an example
(Hirth (2010))
Parkinson’s disease, introduced mitochondrial dysfunction in cholinergic, dopaminergic; and serotonergic neurons.
What was the effect on mitochondrial dysfunction in cholinergic, dopaminergic; and serotonergic neurons?
Only affected dopaminergic.
What does cell lineage mean?
All cells derive from one.
J. Sutton was able to trace this tree in C. Elegance, got a Nobel Price for it.
