[Drosophila] Three year PhD Studentship in MRC Human Genetics Unit, Edinburgh

[Liam Keegan]

Dept/School  	 Human Genetics Unit, Medical Research Council
Project Title    Drosophila Screen for Regulators of RNA editing
Project Supervisor(s) 	Dr L Keegan, Dr M O’Connell
Application Deadline 	22 August 2008

The MRC Human Genetics Unit is offering a three year PhD studentship 
funded by the Scottish Motor Neurone Disease Association working under 
the supervision of Dr Liam Keegan. This excellent opportunity would suit 
a student finishing an MSc project on Drosophila or a student graduating 
with a good training in Genetics and Developmental Biology and some 
experience of working with Drosophila or another efficient model organism.

The project is based in lab studying RNA editing. This is a step in RNA 
processing that affects the expression levels and the amino acid 
sequences of vertebrate glutamate receptors. Loss of RNA editing has 
been reported in motor neurones of ALS patients (Kawahara (2004) Nature 
427, 801). and following ischaemia in central neurons (Peng (2006) 
Neuron 49, 719). Glutamate is the major excitatory neurotransmitter in 
vertebrate CNS and loss of the edited forms of vertebrate glutamate 
receptors is expected to promote neuron death by allowing excessive 
calcium influx.

Vertebrates have multiple genes encoding the relevant RNA editing 
enzymes, called ADARs, whereas the fruit fly Drosophila has a single 
Adar gene. The project will take advantage of Drosophila to carry out a 
genetic screen for proteins that interact with and regulate the activity 
of these RNA editing enzymes. As in vertebrates flies mutant for the 
Adar gene lose RNA editing in a range of target transcripts encoding ion 
channel subunits. The flies have locomotion defects from birth, reduced 
viability and show age-dependent neurodegeneration. All phenotypes are 
rescued by expression of either Drosophila or human ADARs.

Adenosine to inosine RNA editing targets stretches of double stranded 
RNA which may be either short hairpins within pre-mRNAs or long 
stretches of dsRNA formed by transposable elements or by antisense 
pairing of complementary transcripts. Site-specific editing within 
pre-mRNAs affects RNA splicing and recodes open reading frames to 
produce ion channel variants. Non-specific editing within long dsRNAs 
antagonizes the RNA interference that is triggered by these dsRNAs. The 
screen will potentially contribute to understanding both these roles of 
ADARs.

The screen will identify regulators of ADAR activity in the fly by 
looking for modifiers of viability in Adar loss of function mutants that 
have reduced viability already or by looking for suppressors of 
lethality caused by early overexpression of ADAR (Keegan (2005) Embo J 
24, 2183). The screen uses a standard, efficient method in Drosophila 
that begins with looking for effects of larger heterozygous deficiencies 
and then refining the effects down to specific genes. The objective is 
to identify regulators that are conserved and likely to be informative 
about the regulation of editing in vertebrate neurons and to focus on 
the roles of these in regulation of ADAR activity and in neuroprotection.

Kawahara (2004) Nature 427, 801
Peng (2006) Neuron 49, 719
Keegan (2005) Embo J 24, 2183

Lab information is available at:
www.hgu.mrc.ac.uk/users/Liam.Keegan/Home.html
www.hgu.mrc.ac.uk/Research/OConnel/crrt.html

Funding Notes
This 3 year PhD studentship will be funded by the Scottish Motor Neurone 
Disease Association and we ask potential applicants to note that while 
there are eligibility criteria for this studentship, we encourage all 
qualified EU students to apply.
Further information regarding eligibility can be found on 
www.hgu.mrc.ac.uk/StaffInf/Studentships/residency.html
The studentship offers an attractive stipend and a comprehensive 
transferable skills training programme.

Applicants should submit a covering letter explaining why you are 
interested in applying. Applications should include a full up-to-date 
C.V. (include vacation address), and names and addresses of two academic 
referees, sent by 22 August 2008 to: student-admin from hgu.mrc.ac.uk or 
Studentships, MRC Human Genetics Unit, Western General Hospital, Crewe 
Road, Edinburgh EH4 2XU.

-- 
Dr. Liam Keegan                      Tel No. ++ 44 (0)131 467 8417

MRC Human Genetics Unit              Fax No. ++ 44 (0)131 467 4856

Western General Hospital
Crewe Road

Edinburgh EH4 2XU

UK

http://www.hgu.mrc.ac.uk/

http://www.hgu.mrc.ac.uk/users/Liam.Keegan/Home.html

http://www.hgu.mrc.ac.uk/Research/OConnel/