Transcriptional regulation of the neuropeptide galanin : special reference to axotomy

Sammanfattning: Galanin is a neuropeptide which is located in both the central and peripheral nervous system. In peripheral neurones, this peptide is thought to be involved in influencing pain sensation after nerve injury (neuropathic pain) and also in the regeneration of peripheral nerves. Following axonal injury, there is a dramatic rise in the levels of galanin rnRNA and immunoreactivity in the neuronal cell bodies of sensory and autonomic ganglia. In the dorsal root ganglia (DRGs), this upregulation takes place primarily in small to medium sized neuronal cell bodies. The goal of this thesis was to characterise some of the regulatory pathways which influence galanin transcription, with particular focus on the regulation of this peptide after nerve injury. We have found that both leukaemia inhibitory factor (LIF) and nerve growth factor (NGF) contribute to the transcriptional regulation of galanin in DRGs after sciatic nerve transection, and that these two factors may interact. Indeed, we have shown that the action of LIF in mediating this effect is dependent on the absence of NGF. Furthermore, we have found that a proximal 2.2 kb region of the rat galanin promoter is responsible for axotomy-induced regulation within the DRG. This region of the galanin promoter is responsive to LIF treatment in vitro, whereas the 1.4 kb region is not. Moreover, the region between -2.2 and -1.4 kb contains a strong repressor element which is active in primary sensory neurones in culture, but not in epithelial, placental or undifferentiated neuronal cell lines. This thesis is based on the work of five communications, which will describe in detail the results outlined above. In addition, unpublished preliminary studies are presented in the summary of this thesis which contribute to the analysis of the galanin regulatory region.