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Small Ubiquitin-related Modifier (SUMO) is a 97-amino acid protein that can be covalently conjugated to lysine residues of target proteins via an enzymatic cascade analogous to the ubiquitin pathway. A major function of SUMO conjugation is to modify protein–protein interactions but many substrates remain to be identified and the roles of SUMOylation in neuronal differentiation, growth and maturation have not been determined. While many effects of SUMOylation are expected to be on the regulation of transcription, a well-documented role for this signalling pathway, this project will also focus on SUMO effects on extranuclear proteins and especially proteins at nascent and developing synapses.
Aim: we want to define how modulation of the SUMO pathway both inside and outside the nucleus effects neuronal development and morphology with particular emphasis on dendritic spine formation and synaptic maturation.
Hypothesis: Protein SUMOylation is a fundamental signaling pathway in neuronal growth and development and in spine and synapse formation.
Outline plan: Initially we shall determine the developmental profiles of specific SUMO pathway proteins and then either increase or block their expression.
Methods: Techniques will include neuronal cell culture, viral expression of exogenous SUMO proteins, RNAi, and live and fixed cell confocal imaging. The host lab has many years experience in all of these protocols and extensive training will be provided.
Example experiments:
Developmental expression of SUMO pathway proteins (e.g. SUMO-1, SUMO2/3, Ubc9, SENP1, SENP2)
Subcellular compartmentalisation of changes in SUMO proteins e.g. nuclear, non-nuclear, synaptic etc
Correlation to developmental milestones in neuronal morphology (e.g. neurite extension, dendritic arborisation, spine formation).
Effects on overexpression of SUMO pathway proteins on key stages of neuronal development.
Effects of selective RNAi knock down of SUMO pathway proteins.
Identification of SUMOylated target proteins at different time points in development (e.g. proteomics of different cellular compartments)
Outcomes: This work will define the roles of SUMO in neuronal development.
Funding Notes:
For funding opportunities please see the SWDTP site at:
http://www.bristol.ac.uk/prospectus/postgraduate/2012/swdtp/
References:
Martin, S., Wilkinson, K. A., Nishimune, A. and Henley, J. M. (2007) Emerging extranuclear roles of protein SUMOylation in neuronal function and dysfunction. Nat Rev Neurosci, 8, 948-959.
Wilkinson, K. A., Nakamura, Y. and Henley, J. M. (2010) Targets and consequences of protein SUMOylation in neurons. Brain Res Rev, 64, 195-212.