The de Moor Lab
Research
The research in my laboratory focusses on translational control, mRNA localisation and regulated mRNA stability by the 3' untranslated region (3'UTR) of the mRNA. Translational regulation and mRNA localisation by the 3' UTR is especially common in developmental systems, such as Drosophila development and during oocyte development. Recently 3' UTRs have also been demonstrated to play a role in synaptic plasticity in neurons and in the cell cycle. We use Xenopus oocytes and embryos as well as tissue culture systems to investigate the role of translational control and mRNA localisation in development and the cell cycle. Ultimately, we would like to fully characterise the translational control of an mRNA by its 5' and 3' UTRs and elucidate the structure of its native mRNA-protein (mRNP) complex in both its active and inactive state. To this end, we are collaborating closely with the research groups of Professor Willis and Dr. Bushell. Our work is likely to have implications for cancer therapy, fertility treatment and stem cell research.
Three forms of translational regulation are currently under investigation in my laboratory:
a) Translational activation by cytoplasmic polyadenylation
This can be mediated by a variety of elements in the 3' UTR, including the cytoplasmic polyadenylation element (CPE). Elongation of the poly(A) tail in the cytoplasm generally leads to upregulation of translationally repressed mRNAs. Cytoplasmic polyadenylation is especially common in oocytes and in early development.
b) Translational repression by protein binding elements in the 3' UTR
Proteins binding to the 3' UTR can repress translation either by interacting with initiation factors or the ribosome to form an abortive translation initiation complex (see maskin model below), or by completely hiding the mRNA from the translational machinery. We are studying several repression elements and their binding proteins to determine their mechanism of action.
c) Translational repression by microRNAs
MicroRNAs are short endogenous 20-23 nt RNAs that are in a large RNA-protein particle called the RNA interference silencing complex (RISC). They cause degradation of their target mRNA if the complementarity between the mRNA and the microRNA is perfect, and can cause translational repression if there are a few mismatches. There are hundreds of microRNAs encoded in the human genome and a large number of mRNAs is expected to be regulated this way.
The following projects are currently active in my laboratory:
1. Translational regulation in oogenesis
During oogenesis and early development in Xenopus, transcription is repressed and gene expression is largely regulated by translational control. Cytoplasmic polyadenylation plays a large role in this regulation. In most cases, cytoplasmic polyadenylation is mediated by elements close to the end of the mRNA, which cooperate with the poly(A) signal. The best studied element with this activity is the cytoplasmic polyadenylation element, which can mediate cytoplasmic polyadenylation during oocyte maturation, during the early embryonic cell cycles and in neurons.
During my stay in the Richter lab, I contributed to the development of the maskin model for translational repression of cyclin B1 mRNA in immature oocytes. This model proposes that CPEB binds to the cytoplasmic polyadenylation elements in the cyclin B1 mRNA and recruits a protein called maskin that blocks assembly of the full cap binding translation initiation complex by associating with eIF-4E. The release of this block is mediated by cytoplasmic polyadenylation.
We have now discovered that maskin itself is translationally regulated by the 3' UTR of its mRNA and characterised control elements and their binding proteins. We are currently investigating the mechanism of this regulation.
2. Regulatory complexes on mRNAs involved in cell cycle control
A large number of cell cycle regulatory mRNAs is translationally controlled by their 3' UTRs during the meiotic cell cycle. We are currently using proteomic approaches to investigate whether there are similarities in the protein complexes binding to these 3' UTRs.
3. Mechanism of microRNA mediated translational control
The mechanism of microRNA mediated translational control is not clearly delineated. In collaboration with Dr Martin Bushell we are trying to shed some light on this question.
4. Translational control in cell adhesion
In collaboration with Dr. Peter Jones (Biomedical Sciences), we have recently shown that some of the translational regulators that we study are specifically localised during cell adhesion. We are currently attempting to demonstrate that translational control plays a role in this process.
Dr Cornelia de Moor - Lecturer in RNA Biology
PhD University of Utrecht working with Dr. Maarten Jansen
1994-1999 Postdoctoral Fellow with Professor Joel Richter, University of Massachusetts
2000-2005 Lecturer in Molecular Biology, School of Biomedical Sciences, University of Nottingham
2005-2010 Lecturer in RNA Biology, School of Pharmacy, University of Nottingham
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