Hollen, Kristen Margaret; (1997) Expression and DNA binding of AP-1 proteins in the central nervous system following neuronal injury. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Pathophysiological activation of NMDA receptors in the rat striatum in vivo leads to the rapid molecular induction of immediate early gene (IEG) transcription factors which may regulate the expression of downstream genes important for neuronal survival. Fos and Jun family proteins which make up the AP-1 transcription factor complex are amongst the earliest genes induced in the quinolinic acid (QA) lesioned rat striatum. This study characterizes the complete temporal pattern of Fos family protein expression between two and 30 hour following striatum QA lesion using Western blot analysis with antibodies specific to each protein. c-Fos expression is rapid and transient followed by the sequential expression of FosB and ΔFosB for more prolonged periods. This study demonstrates for the first time the expression of ΔFosB after striatal QA lesion, and localizes by immunocytochemistry both FosB and ΔFosB proteins concurrently present in the same neurons. Examination of lesion-induced mRNA by RT- PCR proves that ΔfosB is derived from the alternative splicing of the fosB gene. There is constitutive expression of Fra-1, Fra-2, and three additional Fos-related proteins which have not previously been described. Electrophoretic mobility shift assays (EMSA) show that Fos family proteins expressed after striatal lesion are involved in binding to the AP-1 consensus sequence within the first intron of the nerve growth factor gene, which may have important consequences for neuronal survival. The binding pattern of lesion- induced proteins to the NGF promoter element is compared to various related DNA promoter regulatory elements. The interactions of AP-1 with other transcription factors such as the activated glucocorticoid receptor, ATF-2, and CREB are investigated by EMSA supershift studies, and the functional importance of these transcription factor interactions are discussed in respect to the control of the nerve growth factor gene following striatal injury.

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