The role of miRNA-gene interactions in regulating neuronal function
MicroRNAs (miRNAs) are a class of small endogenous non-coding RNA molecules that act as post-transcriptional regulators in many developmental and physiological processes. MicroRNAs are important in neural development and function, and has been implicated to have roles in synaptic plasticity, neurogenesis Alzheimer’s disease, Parkinson’s disease, Rett syndrome, addiction and schizophrenia (for review see 1). In addition, miRNAs have been shown to direct the pluripotency and differentiation processes of stem cells, including the derivation of neurons from stem cell populations 2. Levels of specific miRNAs are significantly altered after a sciatic nerve lesion, suggesting that miRNAs may contribute to regenerative processes after neuronal injury 3. However the pathways that are manipulated by these miRNAs during neural regeneration remain relatively unknown.
Very powerful techniques for analysing the transcriptome now exist. One such technology is HIgh-Throughput Sequencing of RNA isolated by CrossLinking ImmunoPrecipitation (HITS-CLIP) 4. HITS-CLIP allows us to identify the direct microRNA-gene target interactions that occur in regenerating neurons thereby uncovering the functional effects of the miRNAs in the nervous system. Using this technology, we have identified miRNA-gene targets that are specific for a microRNA miR-21. The project will investigate the function of these targets in primary neuron models and in embryonic or induced pluripotent stem cell models using state-of-the-art molecular tools (e.g. lentiviral vectors, RNAi), confocal microscopy to determine the subcellular localisation of the miRNAs and selected genes within neurons, and biochemical or electrophysiological methods to assess neuronal function following gene perturbation.
This project will help us further understand the role of miRNAs in neuronal function, particularly in nerve regeneration, neurogenesis and stem cell differentiation. The student will have access to excellent supervision, expertise, resources and practical support in the laboratory and gain training in a diverse range of techniques such as cutting-edge molecular biology, viral vectors, stem cell culture, neuron derivation and cell imaging.
When applying please select ’Neuroscience PhD’ within the Faculty of Health Sciences.
1 Saba R, Schratt GM (2010) MicroRNAs in neuronal development, function and dysfunction. Brain Res 1338:3-13
2 Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T, Li Y, Lee-Messer C, Dolmetsch RE, Tsien RW, Crabtree GR (2011) MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476(7359):228-31
3 Strickland IT, Richards L, Holmes FE, Wynick D, Uney JB, Wong LF (2011) Axotomy-induced miR-21 promotes axon growth in adult dorsal root ganglion neurons. PLoS One 6(8):e23423
4 Licatalosi, D.D., et al. (2008) HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456, 464-469