http://www.youtube.com/user/BritishHeartFound#p/u/0/djFb8PGS34g

Compare and contrast the Drosophila and Zebrafish as animal systems for the study

of human disease.

April, Laura, Alaa

What’s an Animal System?

An animal system is a living, non-human animal used for the research and investigation of

human disease

Drosophila Melangaster

Drosophila MelangasterDrosophila Melangaster

Fruit fly

One of the first to be used

Similarities to human genes

Used for high throughput drug screening

Advantages

Fast development

Carry out sophisticated loss-of-function and gain-of-function genetic analysis

Easy and rapid genetic analysis

Short generation time

High fecundity

Easy maintenance in large numbers

Mutants are easier to obtain

Neurodegenerative Diseases

Generation of transgenic Drosophila which over express mutated proteins causing them to develop degenerative diseases allowing us to use them as models for Alzeimers and Huntingtons disease.

Animal models have helped us find possible cause of HD: (1) Expansion of unstable CAG repeat (2) Effect of Quasi-pure polyglutamine tracts (3) Implications to Caspases 1 & 3

Parkinson’s disease

Disease background:-Progressive degenerate disorder of the CNS-Idopathic disorder-Symptoms are movement related-Dominant cause = mutations of alpha synuclein

Animal model:-Flies with mutant alpha synuclein have developed motor impairment-Research on Parkin specific mutations in association with indirect fly muscles

Spinal Muscular Atrophy (SMA)

Disease background:-Characterised by degeneration of motor neurons-Mutation of Survival Motor Neuron(SMN) gene in humans

Model:-Model mimics phenotype of human disorder-The Fibroblast Growth Factor (FGF) signalling pathway in humans is the homolog to the drosophilas’ SMN -SMN gene mutation results in:1)Reduced viability 2)Decreased motility 3)Develops muscular atrophy in the adult thorax

Heart DiseaseDisease background -Umbrella term for many heart related diseases-Leading Cause of death in the UK -Examples: CHD, Cardiovascular disease and Heart failure.

Animal Model-New research field -Less complicated circulatory system than in humans-From screening 7,061, 500 were found to be associated with cardiovascular disorders

-Mutant flies have low levels of PE-Initiate a new mechanism for synthesising fats-This is the protein SREBP which activates enzymes that synthesise fats-High levels of this protein along with triglycerides and heart damaging fats.-Fat accumulation and distribution to the membrane leads to heart problems.-Inhibiting this protein allows restoration of fat balances and therefore reduced heart malfunctions.

ZebrafishZebrafish

Zebrafish

Danio rerio

Tropical freshwater fish

Genetically and morphologically similar to humans

Good human disease models

Advantages

Short generation time (especially for a vertebrate)

Transparent embryo

Genetic tractability

Easy manipulation

Spinal Muscular Atrophy(SMA)

The Morpholino Spinal Motor Neuron(SMN) protein gene is the faulty gene is some forms of SMA

This has been researched using gene knockdowns of the SMN gene in Zebrafish embryos

Morphant axons exhibit motor axon specific pathofinding defects with no increase in the rate of apoptosis in motor neurons.

Concluding - SMN has an important function in motor axon development and maintenance

Heart Disease

Special ability to regenerate damaged heart

Our capability of developing our heart once should mean we can do it again?

Fast heart development - 12 hours

Transparent embryo allows viewing of heart and blood vessel development

Similarities in key genes and chemical messengers means we can try to replicate the process in humans

Drosophila Vs.

Zebrafish

Compare

Both have high Fecundity

Both used for drug discovery

Both develop rapidly - Allowing rapid genetic analysis

Embryos develop outside and not in the mother therefore developmental stages can be monitored

Easy access with fewer ethical objections

ContrastInvertebrate

7-19 generation time

Micromanipulation is limited

Non-transparent embryo

DNA content - 180 million

58% genetic similarity to humans

Vertebrate

3-4 months generation time

Micromanipulation is greater

Transparent embryos

DNA content - 1900 million

82% genetic similaritiey to humans

Drosophila Zebrafish

Conclusion - why we think Zebrafish are better models.

Zebrafish is a more reliable study for heart disease

They are vertebrates

Greater genetic similarities

Similar organ systems

Similar developmental pathways

Females are easier to work with as they are larger

References Peter.J.Russel. Essential I-Genetics (first edition)Pearson education

Griffths, Miller, Suzuki, Lewontin & GelbartAn introduction to genetic analysis (7th edition)W.H.Freeman

http://www.bhf.org.uk/British heart foundation

Modeling spinal muscular atrophy in Drosophila links Smn to FGF signalingAnindya Sen1, Takakazu Yokokura1, Mark W. Kankel1, Douglas N. Dimlich1, Jan Manent1, Subhabrata Sanyal2, and Spyros Artavanis-Tsakonas1,3

Richard Butler In vivo analysis of neurological disease mechanisms in zebrafish.Thesis 15014

http://www.nature.com/ng/journal/v39/n5/full/ng0507-589.html

http://www.ncbi.nlm.nih.gov/pubmed/11206415

http://pubs.acs.org/subscribe/journals/mdd/v07/i06/html/604feature_ma.html

http://genome.cshlp.org/content/9/2/99.long

http://www.statistics.gov.uk/articles/hsq/hsq28_death.pdf

http://www.shef.ac.uk/mediacentre/index.html

Q & A