The human body is composed of trillions of cells that carry out precise roles, from fighting infections, to transmitting nerve signals or forming a protective barrier to the environment. In order to carry out these many functions, cells need to organize their inner components, including organelles (e.g. the nucleus, mitochondria) and different kinds of molecular ‘machines’, at precise locations inside the cell. When this organization is defective, it can prevent cells from working properly and predispose us to developing a range of diseases, from neuromuscular disorders to cancer.
We aim to understand how cellular organization in influenced by the subcellular localization of messenger RNA (mRNA), molecules that carry the genetic information for making proteins. The intracellular trafficking and localized-translation of messenger RNA transcripts has emerged as a key mechanism for dictating protein distribution in cells. Using high-resolution microscopy imaging, we have previously shown that RNAs often exhibit specific localization patterns (see Figure 1, below). By analogy to global postal services or the transit systems of large cities, RNA localization is dictated by a complex network of ‘zip-code’ targeting elements residing within the RNA molecule, which are recognized by transport machineries containing RNA binding proteins. Our objectives are to:
> Dissect the mechanisms by which RNAs are localized to specific subcellular structures.
> Understand the impact of RNA localization pathways on normal cellular function.
> Determine how disruption of these processes contributes to disease.
For our studies, we use a combination of human cellular models, as well as an experimentally powerful in vivo model system, the fruit fly Drosophila melanogaster. Insights gained using genetically tractable model organisms, such as fruit flies, have been instrumental in understanding many essential cellular processes and disease mechanisms. We combine the versatility of fly genetics, high-throughput molecular imaging and functional genomics strategies, as well as bioinformatics approaches, to dissect RNA localization mechanisms.
Figure 1. Examples of localized RNAs in Drosophila embryos
(blue = RNA, red = DNA/nuclei).
Projects and Funding Sources
> Studying mRNA targeting to the mitotic apparatus.
Funded by the Canadian Institutes of Health Research.
> Epithelial cell polarity regulation by localized mRNAs.
Funded by the Candian Cancer Society Research Institute.
> Defining the mechanism of RNA targeting to extracellular vesicles.
Funded by the Cancer Research Society (Team project with Janusz Rak / Nada Jabado).
> Defining the conserved functions of RNA binding proteins in stress granule biogenesis.
Funded by ALS Canada-Brain Canada.
> The RNA zipcode discovery pipeline: novel tools for molecular targeting at the subcellular level.
Funded by Genome Canada (Team project with Mathieu Blanchette / Jérôme Waldispühl).
> A Comprehensive Functional Map of Human Protein-RNA Interactions.
Funded by the US National Human Genome Research Institute/National Institutes of Health (Team project with Brenton Graveley / Gene Yeo / Chris Burge / Xiang Dong Fu).
In addition to these competitive research grants, several of our trainees also hold institutional, provincial or national scholarships to support their work (see Personnel section). We thank all of these agencies and foundations for their generous support!
For more information about our research, or if you would like to join our team, please contact Dr. Lécuyer.