The Osterweil lab is recruiting a motivated individual to fill a postdoctoral position in cellular neuroscience and bioinformatics. You will be joining the exceptional group of scientists in the Centre for Discovery Brain Sciences and the Simons Centre for the Developing Brain at the University of Edinburgh, recently ranked as the 16th best university in the world. You will be working in Edinburgh, one of the world’s most liveable cities with access to world-class cultural activities, UNESCO Heritage sites and unparalleled outdoor experiences. The laboratory’s research sits at the interface of cellular neuroscience and disease, seeking to address the role of mRNA translation in autism-related neurodevelopmental disorders. You will use cutting edge approaches such as TRAP-seq, Ribo-seq and scRNA-seq to discover how alterations in specific neural circuits contribute to disruptions in circuit function and behavior in animal models of autism. This Wellcome Trust funded position will use these approaches to answer critical questions about how ribosome expression changes mRNA translation in hippocampal and cortical circuits, and how this process may be targeted for therapeutic intervention in mouse models of autism. The post requires relevant experience in bioinformatics analysis of RNA-seq datasets, and experience with scRNA-seq datasets is desired. Candidates must have a PhD in cell biology, neuroscience or a related topic either obtained or expected within 6 months of the start of the contract. This is a full-time post, and start date is flexible. Applications will be reviewed on a rolling basis with a soft deadline of Aug 21. Interested applicants should send a CV and letters of reference to Emily.osterweil@ed.ac.uk. Lab website: https://www.osterlab.org/ University of Edinburgh: https://www.ed.ac.uk/ Simons Centre for the Developing Brain: https://www.sidb.org.uk/ Centre for Discovery Brain Sciences: https://www.ed.ac.uk/discovery-brain-sciences Further Reading 1) Thomson SR*, Seo SS*, Barnes SA✝, Louros SR✝, Muscas M, Dando O, Kirby C, Hardingham GE, Wyllie DJA, Kind PC, and Osterweil EK. Cell type-specific translation profiling reveals a novel strategy for treating fragile X syndrome. Neuron. 2017 Aug 2; 95(3):550-563.e5. doi: 10.1016/j.neuron.2017.07.013. 2) Stoppel LJ, Osterweil EK, and Bear MF. The mGluR Theory of fragile X syndrome. Fragile X Syndrome: From Genetics to Targeted Treatment. Willemsen, R. & Kooy, F. (Eds.). Academic Press, 2017. ISBN: 0128045078, 9780128045077. 3) Asiminas A*, Jackson AD*, Louros S†, Till SM†, Spano T, Dando O, Bear MF, Chattarji S, Hardingham GE, Osterweil EK, Wyllie DJA, Wood ER, and Kind PC. Sustained correction of associative learning deficits following brief, early treatment in a rat model of Fragile X Syndrome. Science Translational Medicine. 2019 May 29;11(494). pii: eaao0498. doi: 10.1126/scitranslmed.aao0498.

Inflammation is a key component of the innate immune response. Primarily designed to remove noxious agents and limit their detrimental effects, the prolonged and/or inappropriately scaled innate immune response may be detrimental to the host and lead to a chronic disease. Indeed, there is increasing evidence suggesting that a chronic deregulation of immunity may represent one of the key elements in the pathobiology of many brain disorders. Microglia are the principal immune cells of the brain. The consensus today is that once activated microglia/macrophages can acquire a wide repertoire of profiles ranging from the classical pro-inflammatory to alternative and protective phenotypes. Recently, we described a novel ribosome-based regulatory mechanism/checkpoint that controls innate immune gene translation and microglial activation involving RNA binding protein SRSF3. Here we will discuss the implications of SRSF3 and other endogenous immune regulators in deregulation of immunity observed in different models of brain pathologies. Furthermore, we will discuss whether targeting SRSF3 and mRNA translation may open novel avenues for therapeutic modulation of immune response in the brain.

Biologists have recently come to appreciate that eukaryotic cells are home to a multiplicity of non-membrane bound compartments, many of which form and dissolve as needed for the cell to function. These dynamical “condensates” enable many central cellular functions – from ribosome assembly, to RNA regulation and storage, to signaling and metabolism. While it is clear that these compartments represent a type of separated phase, what controls their formation, how specific biological components are included or excluded, and how these structures influence physiological and biochemical processes remain largely mysterious. I will discuss recent experiments on phase separated condensates both in vitro and in vivo, and will present theoretical results that highlight a novel “magic number” effect relevant to the formation and control of two-component phase separated condensates.

Silencing of FMR1 and loss of its gene product, FMRP, results in fragile X syndrome (FXS). FMRP binds brain mRNAs and inhibits polypeptide elongation. Using ribosome profiling of the hippocampus, we find that ribosome footprint levels in Fmr1-deficient tissue mostly reflect changes in RNA abundance. Profiling over a time course of ribosome runoff in wild-type tissue reveals a wide range of ribosome translocation rates; on many mRNAs, the ribosomes are stalled. Sucrose gradient ultracentrifugation of hippocampal slices after ribosome runoff reveals that FMRP co-sediments with stalled ribosomes, and its loss results in decline of ribosome stalling on specific mRNAs. One such mRNA encodes SETD2, a lysine methyltransferase that catalyzes H3K36me3. Chromatin immunoprecipitation sequencing (ChIP-seq) demonstrates that loss of FMRP alters the deployment of this histone mark. H3K36me3 is associated with alternative pre-RNA processing, which we find occurs in an FMRP-dependent manner on transcripts linked to neural function and autism spectrum disorders.