About the Project
Background: To mount an immune response, host organisms must first recognize the pathogen with which they are infected. The first line of defense against pathogen infection in animals is provided through the innate immune response. Many aspects of this response are conserved in invertebrates making the fruitfly Drosophila with its sophisticated genetic tools a model of choice. The fundamental knowledge obtained about the innate immune response in fruitflies has even been recognized by a Nobel…
prize.
Recently, the Drosophila Down syndrome cell adhesion molecule (Dscam) gene has been shown to act as pattern recognition receptor in phagocytosis, in addition to its role in neuronal wiring [1, 2]. The Dscam gene generates through alternative splicing over 36'000 different isoforms by inclusion of a single exon in each of the variable regions. Intriguingly, the splicing pattern of Dscam changes upon infection to express isoforms with a higher affinity towards the pathogen in mosquitoes [3]. We anticipate that Dscam splicing is also altered in Drosophila upon pathogen exposure to dramatically increase inclusion of specific isoforms. We currently don't know the identity of the pathogen molecules recognized by Dscam, or how pathogens impact on adapting Dscam alternative splicing for pathogen recognition and if the same mechanism is also used in the human innate immune response.
Objectives:
- Identify pathogens and conditions that induce preferential inclusion of single variable exons in Drosophila Dscam
- Determine pathogen components that are recognized by Dscam and impact on its alternative splicing
- Determine the mechanism(s) through which pathogens impact on alternative splicing regulation
Project description: From a wide array of pathogens available from the Institute of Microbiology and Infection at the University of Birmingham we will first identify those that induce inclusion of a narrow range of exons in the three variable regions as they are indicative of high affinity interactions. For this analysis we developed highly efficient Molecular Biology tools, including high throughput sequencing for efficient analysis [4].
Once we have obtained a broader choice of pathogens we will identify the bacterial molecules impacting on Dscam alternative splicing and determine if they bind to Dscam using genetic, molecular and biochemical approaches.
Alternative splicing is thought to provide a major mechanism for adaptation of cell function to changing environments, e.g. during infection. The Dscam splicing pattern is initially established in a predefined ratios, but probabilistically at a cellular level [4, 5]. We will establish a GFP-based Dscam alternative splicing reporter to identify the pathways, how pathogens lead to adaptive changes in alternative splicing during an innate immune response.
For more information about research in our laboratory, please visit:
References
[1] Watson FL et al (2005) Science 309: 1874.
[2] Hemani Y and Soller M (2012) Biochem Soc Trans 40: 804.
[3] Dong Y et al (2006) PLoS Biology 4: e229.
[4] Haussmann IU et al. (2019) NAR 47:1389.
[5] Miura SK et al (2013) Cell 155:1166.
Eligibility
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in Molecular Genetics or a related area. Candidates with experience in Drosophila genetics or with an interest in mRNA processing are encouraged to apply.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How to Apply
To be considered for this project you MUST submit a formal online application form – on the application form select PhD Genetics. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester
If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester
Funding Notes
This project has a Band 1 (low) fee. Details of our different fee bands can be found on our website View Website
References
Ustaoglu, P., McQuarrie, D., Rochet, A., Haussmann, I.U., Dix, T.C., Devaud J.M., Arnold, R. and Soller, M. (2024) Memory consolidation in honey bees is enhanced by down-regulation of Down Syndrome Cell Adhesion Molecule and changes its alternative splicing. Frontiers of Molecular Neuroscience 16: 1322808.
Ustaoglu, P., Haussmann, I.U., Torres-Mendez, A., Liao, H., Arnold, R., Irimia, M. and Soller, M. (2019) Srrm234, but not canonical SR and hnRNP proteins drive inclusion of Down Syndrome Cell Adhesion Molecule exon 9 variable exons. RNA 25: 1353-65.
Haussmann, I. U., Ustaoglu, P., Brauer, U., Hemani, Y., Dix, T. and Soller, M. (2019) Plasmid-based gap-repair recombineered transgenes reveal a central role for introns in mutually exclusive alternative splicing of Down Syndrome Cell Adhesion Molecule exon 4. Nucleic Acid Research 47:1389-1403.
Hemani, Y. and Soller, M. (2012) Mechanisms of Drosophila Dscam mutually exclusive splicing regulation. Biochem. Soc. Trans. 40: 804-9.