Role of AP-1 Proteins in Glucocorticoid Regulation of Tyrosine Hydroxylase Expression during Early Ontogeny

Abstract

Elevated glucocorticoid levels during the sensitive period of early ontogenesis cause long-term changes in the functioning of neurotransmitter systems and the functions they regulate. One such system is the noradrenergic system, whose activity depends on the effects of stress or hormonal therapy during perinatal ontogenesis, altering stress response and psycho-emotional reactions in adult animals. Tyrosine hydroxylase (TH), a key enzyme in norepinephrine synthesis, is induced by glucocorticoids in the brain of fetal rats but remains unaffected by hormone administration on the 8th day of life. To evaluate the involvement of AP-1 transcriptional complex proteins in the age-dependent regulation of TH, we examined the relationship between the expression levels of the genes and proteins of the Jun and Fos families during and outside of hormonal induction of the enzyme gene. Hormonal induction of the TH gene and protein expression was found to occur during the periods of elevated Jun family gene expression (JunB, c-Jun, JunD) relative to Fos family genes (c-Fos, FosB) in the brainstem of 20-day-old fetuses and 3-day-old rat pups, and was absent when this ratio decreased on the day 8 of life. Chromatin immunoprecipitation followed by qPCR (ChIP-qPCR) demonstrated that, following dexamethasone administration on postnatal day 3, the number of the JunB protein-bound AP-1 sites on the Th gene promoter was significantly higher compared to the day 8. Consequently, the period of hormonal induction is accompanied by the relative predominance of the Jun/Jun homodimeric complexes on the Th gene promoter, which activate transcription of the regulated genes. This is in contrast to the day 8 of life, when the balance of Jun/Fos complexes shifts toward formation of heterodimers that do not alter transcription. The established dynamics of the ratio of AP-1 complex proteins may underlie the age-dependent manifestation of glucocorticoid induction of TH expression in vivo in the perinatal brain.