Cytoplasmic regulation of mRNAs during early vertebrate development: Mechanisms and roles of RNA-protein interactions

Lead Research Organisation: MRC Human Genetics Unit

Abstract

The control of protein production in the body is vital for health. All proteins are products of particular genes and these have to be turned on at the right times, places and in the right amount to ensure proper cell function. This process is called gene expression. One level at which gene expression is controlled is called translation, in which mRNA templates copied from genes are used as instructions to build proteins. Recent research has shown that when the processes that control translation fail, it can lead to a wide variety of human diseases including cancers, neurological, metabolic and reproductive disorders.|By focusing on related families of translational regulators, we aim to discover the general mechanisms by which these classes of proteins function and also to increase our knowledge of pathways leading to a variety of genetic disorders. This may ultimately lead to better treatment.

Technical Summary

The overall scientific aim of this program is to understand the fundamental mechanisms and roles of regulating mRNA translation. Recent data suggests that 40-60% of vertebrate mRNAs are controlled at the level of translation and that breakdowns in this process can lead to disease. Despite this, the roles and underlying mechanisms of translational control are poorly understood. Thus dissecting their contribution to normal biology and human disease is a priority. We focus on three basic questions regarding RNA-protein complexes that regulate translation of specific mRNAs. Firstly, the identification of trans-acting factors that regulate translation. Secondly, the mechanisms by which these RNA-protein complexes function. Thirdly, what are the roles of these RNA-protein complexes in biological processes such as development and in disease.

Publications

10 25 50

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Dickson KS (2001) Poly(A) polymerase and the regulation of cytoplasmic polyadenylation. in The Journal of biological chemistry

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Wilkie GS (2003) Regulation of mRNA translation by 5'- and 3'-UTR-binding factors. in Trends in biochemical sciences

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Sanford JR (2004) A novel role for shuttling SR proteins in mRNA translation. in Genes & development

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Wilkie GS (2005) Embryonic poly(A)-binding protein stimulates translation in germ cells. in Molecular and cellular biology

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Burgess HM (2010) mRNA-specific regulation of translation by poly(A)-binding proteins. in Biochemical Society transactions

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Dinour D (2010) Homozygous SLC2A9 mutations cause severe renal hypouricemia. in Journal of the American Society of Nephrology : JASN

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Gorgoni B (2011) Poly(A)-binding proteins are functionally distinct and have essential roles during vertebrate development. in Proceedings of the National Academy of Sciences of the United States of America

 
Description Biochemical Society
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description Biochemical Society
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description Biochemical Society
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description Biochemical Society
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description BBSRC repsonsive mode
Amount £792,997 (GBP)
Funding ID BB/P022065/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2017 
End 09/2020
 
Description Marie Curie
Amount £185,000 (GBP)
Funding ID MARS 
Organisation European Union 
Sector Public
Country European Union (EU)
Start 04/2017 
End 04/2019
 
Description Program grant
Amount £1,868,414 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2012 
End 03/2016
 
Description Project grant
Amount £293,130 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2011 
End 07/2013
 
Description Project grant PABP5
Amount £657,064 (GBP)
Funding ID BB/J01687X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 02/2013 
End 01/2016
 
Description Wellcome Trust Project Grant (Translational control by the multi-functional Herpes Simplex Virus Type I protein, ICP27)
Amount £225,871 (GBP)
Funding ID 084359 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2008 
End 07/2011
 
Description Wellcome Trust Project Grant (Translational regulation in germ cells, the DAZL family of RNA-binding proteins)
Amount £220,867 (GBP)
Funding ID 081709/Z/06/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2007 
End 03/2012
 
Title In vivo assay for initiation 
Description An assay to determine the contribution of a translation initiation factor in mRNA specific control in vivo 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact only way of determining metric is to look at each paper which cites us and to read in detail to see if for method or other information.... 
 
Title New Xenoups facility 
Description A facility to permit research using Xenopus, a non-mammlain vertebrate model was established. 
Type Of Material Improvements to research infrastructure 
Year Produced 2006 
Provided To Others? Yes  
Impact In addition to our own publications, this facility provides facilitates research for other Edinburgh University Xenopus users enabling their research and fostering a collaborative environment. Collaboration also allows for 3Rs- by reduction (i.e. material/animal can be shared between multiple groups) 
 
Title PABP-specific antibodies 
Description Antibodies which can distinguish between PABP family members in multiple species 
Type Of Material Antibody 
Year Produced 2008 
Provided To Others? Yes  
Impact Has enabled several publications and the securing of future funding 
 
Description HSV-1 
Organisation University of Glasgow
Department Institute of Biomedical and Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have directed the majority of research but have benifited from the facilities and knowledge of our collaborator
Collaborator Contribution Resulted in publications and project grant applications
Impact 20573819 18631144 Another submitted publication under revision
Start Year 2006
 
Description HSV-1 
Organisation University of Glasgow
Department Institute of Infection, Immunity and Inflammation
Country United Kingdom 
Sector Academic/University 
PI Contribution We have contributed to three primary papers, one of which is submitted, two of which are in submission. We have also co-authored a review
Collaborator Contribution A post-doc was in my lab on secondment
Impact We have contributed to three primary papers, one of which is submitted, two of which are in submission. We have also co-authored a review (18631144)
Start Year 2006
 
Description HSV-1 translation 
Organisation University of Glasgow
Department Institute of Infection, Immunity and Inflammation
Country United Kingdom 
Sector Academic/University 
PI Contribution We have contributed to three papers which are submitted or in preparation. One of these was almost entirely from our laboratory. Some reviews on this topic have also been written.
Collaborator Contribution A post-doctoral worker was seconded to my lab.
Impact Several papers publiches, One grant awarded by WT, one awarded by BBSRC
Start Year 2006
 
Description PABP localisation 
Organisation University of Glasgow
Department Institute of Biomedical and Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We have directed the majority of this research but benifited from the knowledge of our collaborator
Collaborator Contribution We have been able to understand how are protein is moved in respeonse to cell stress a paper is in preparation
Impact Work published
Start Year 2008
 
Description PABP phenotypes 
Organisation University of Wisconsin-Madison
Department Department of Biochemistry
Country United States 
Sector Academic/University 
PI Contribution We have provided the majority of the work on understanding the phenotypes caused by PABP loss of function
Collaborator Contribution Allowed experiments to be performed that were not easily within our technical expertise
Impact Work published
Start Year 2008
 
Description SLC2A9 
Organisation Medical Research Council (MRC)
Department MRC Human Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Undertaking assays in oocytes to determine the functional impact of newly identified human mutations
Collaborator Contribution Publications and methodology development
Impact 19926891 Second paper in process of submission
Start Year 2008
 
Description SLC2A9 and Gout 
Organisation Medical Research Council (MRC)
Department MRC Human Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution We established an assay which permitted us to show that SLC2A9 transports urate explaining its association with Gout
Collaborator Contribution This has promoted the adaption of a new assay within the lab
Impact 18327257
Start Year 2007
 
Description SUA and gout 
Organisation Medical Research Council (MRC)
Department MRC Human Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution We set up and performed functional assays using micor-injection of oocytes
Collaborator Contribution We showed that a gene associated with gout can transport urate providing a functional understanding of its link to this condition
Impact 18327257
Start Year 2007
 
Description SUA levels and renal failure 
Organisation Medical Research Council (MRC)
Department MRC Human Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution We utilised an assay which we developed for a previous publication and established a new assay within th elab, this allowed us to identifying the fucntional effect of a mutation which causes renal failure
Collaborator Contribution This project made us explore immunofluroesence in oocytes and has resulted in a technique which we can now use to answer other questions.
Impact 19926891
Start Year 2009
 
Description Tex-19 
Organisation Medical Research Council (MRC)
Department MRC Human Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution We were involved in the basic functional analysis of Tex-19 which was knocked-out in mice.
Collaborator Contribution This has opened up a potential new area that may be subject to a grant application depending on preliminary data
Impact 18802469
Start Year 2007
 
Description Tex-19 
Organisation Medical Research Council (MRC)
Department MRC Human Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution We explored the putative function of Tex19, which was knocked-out in mice as part of the study
Collaborator Contribution This has opened a potential new area of research which maybe the subject of a collaborative grant
Impact 18802469
Start Year 2007
 
Title Antibodies 
Description Have been asked to provide several antibodies commercially, discussions ongoing. 
Type Diagnostic Tool - Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact N/A - not yet in market 
 
Title PABP specific antibodies 
Description Antibodies being licenced to commerical company 
Type Products with applications outside of medicine
Current Stage Of Development Initial development
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact To early to determine 
 
Description Keynote translation 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Keynote talk
Year(s) Of Engagement Activity 2015
 
Description Public Engagment committee 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact As a committee we co-ordinated and organised public engagement events such as the MRC contribution to the science festival.

Difficult to assess, although returning numbers to the science festival suggest that the event has appeal.
Year(s) Of Engagement Activity 2006,2007
 
Description Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact Members of the laboratory (student and post-doc) manned the MRC exhibit at the science festival.

This is difficult to ascertain, children and adults were engaged but the long-term impact is not clear.
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact MRC stand at science festival, designed by units and manned by students and post-docs. In some years I have been dorectly involved in stand design in terms of scientific message.

Unaware
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description Science festival 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact Post-doc on my Senior manned the exhibit at the Edinburgh Science Festival.

Difficult to ascertain the long term impact
Year(s) Of Engagement Activity 2007
 
Description TV appearance (BBC Scotland) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact No measurable feedback was intreview to explain the results of research in response to press release

No measurable feedback
Year(s) Of Engagement Activity 2007
 
Description women in science 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Approximately 2007, panel member in Women in Science Question and Answer session for the Biochemical Society.

Biochemical Society have followed up with articles and information pertaining to careers in science
Year(s) Of Engagement Activity 2007