National Doctoral Programme in
Informational and Structural Biology

In neurons, JNK regulates differentiation as well as apoptotic programs. We have shown that JNK activity in neurons is compartmentalised into distinct pools that are nuclear or neuritic in location. A constitutively active, non-stress responsive pool of JNK resides predominantly in the neurites and modifies cell morphology during neuronal differentiation. A minor stress-sensitive pool of JNK that exhibits stereotypical behaviour, i.e. nuclear translocation on activation, showing preferential access to c-Jun, a critical mediator of neuronal cell death in neurons also exists. Thereby, distinct pools of JNK serve different functions.

In order to better understand the developmental and pathological roles of CNS JNK we have taken a proteomics approach to identify novel JNK targets in the brain as the existing repertoire of JNK substrates is limited and fails to explain the multifunctional actions of JNK in neurons. A strategy combining the use of affinity chromatography or 2D electrophoresis and mass-spectrometry/database searching has revealed a novel family of neuron specific JNK substrates whose expression is highly up-regulated during embryonic and early postnatal CNS development. The role of these proteins in neurite outgrowth, migration and growth cone dynamics is being examined using fluorescence imaging methods. An array of plasmids encoding fluorescently tagged JNK targets, specifically designed to address these questions has been prepared for use in real-time studies in living neurons. Candidate JNK3 targets are also being revealed and functional studies are underway to establish their role in neuronal models of excitotoxicity and developmental cell death. This information should aid in the design of improved therapeutics for diseases relating to neuronal cell death.