The role of Jun transcription factor expression and phosphorylation in neuronal differentiation, neuronal cell death, and plastic adaptationsin vivo

Abstract

1. To investigate the role of the Jun transcription factors in neuronal differentiation, programmed neuronal cell death, and neuronal plasticity, we used phosphorothioate oligodeoxynucleotides (S-ODN) to inhibit selectively the expression of c-Jun, JunB, and JunD. 2. We have shown previously that in contrast to c-Jun, the JunB and JunD transcription factors are negative regulators of cell growth in various cell lines. Here we confirm this finding in primary human fibroblasts. 3. c-Jun and JunB are counterplayers not only with respect to proliferation, but also in cell differentiation. Since JunB expression is essential for neuronal differentiation, we analyzed possible posttranslational modifications of JunB after induction of PC-12 cell differentiation by nerve growth factor (NGF). 4. JunB was strongly phosphorylated after induction of PC-12 cell differentiation with NGF but not after stimulation of cell proliferation with serum. Thus, while cell proliferation is associated with c-Jun phosphorylation, cell differentiation is correlated with JunB phosphorylation. This supports the finding that c-Jun and JunB play antagonistic roles in both proliferation and differentiation. 5. The JunB transcription factor together with the c-Fos transcription factor is also induced in vivo in the suprachiasmatic nucleus (SCN) of rat brain after a light stimulus that induces resetting of the circadian clock. 6. Using antisense oligonucleotides injected into the third ventricle, we selectively cosuppressed the two transcription factors in vivo as shown by immunohistochemistry. Expression of c-Jun, JunD, and FosB was not affected. Inhibition of JunB and c-Fos expression prevented the light-induced phase shift of the circadian rhythm. In contrast, rats injected with a randomized control oligonucleotide showed the same phase shift as untreated animals. 7. In primary rat hippocampal cultures, anti-c-jun S-ODN selectively inhibited neuronal cell death and promoted neuronal survival. This indicates a causal role of c-Jun in programmed neuronal cell death. 8. These findings demonstrate the essential role of inducible transcription factors in the reprogramming of cells to a different functional state. Jun transcription factors play an essential role not only in fundamental processes such as cell proliferation, differentiation, and programmed neuronal cell death, but also in such complex processes as plastic adaptations in the mature brain. The inhibition of neuronal cell death by anti-c-jun S-ODN shows the great therapeutic potential of selective antisense oligonucleotides.

Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes

“…Fourth, we discovered multiple intergenic MeCP2 binding sites within three imprinted loci consistent with MeCP2 organizing imprinted loci into chromatin loops (19). Finally, this study uncovered two new MeCP2 target genes of potential importance to the pathogenesis of Rett syndrome, the immediate-early response gene JUNB (38) and RNASEH2A, mutations of which cause the progressive neurological disorder Aicardi-Goutieres syndrome type 4 (AGS4) (39).…”

Unifying theory of hypoxia tolerance: molecular/metabolic defense and rescue mechanisms for surviving oxygen lack.

“…Both c-fos and c-jun are genes for transcription factors and represent two members of a family frequently referred to as classical "immediate early genes," one of the most rapidly inducible of genes in the cell; their general functional roles are to regulate growth, differentiation, and reprogramming or restructuring of cells in different physiological states. The different members of this gene family are induced to variable degree by various stimuli and can act in a synergistic or opposing manner, suggesting that both the absolute and the relative amounts of different members of the family determine their net effects (51)(52). The c-fos and c-jun protein products are separately inactive; however, as heterodimers, they form a part of the AP1 transcription factor complex and are involved in regulating the expression of a battery of other genes with AP1-binding sites in their promoter regions.…”

“…The c-fos and c-jun protein products are separately inactive; however, as heterodimers, they form a part of the AP1 transcription factor complex and are involved in regulating the expression of a battery of other genes with AP1-binding sites in their promoter regions. This regulatory cascade is considered to orchestrate "adaptive responses" to various stimuli including hypoxia, ischemia, pressure overload, stretch, and several hormones (45,46), all of which, if sustained, are characterized by cellular reprogramming and metabolic reorganization (51)(52)(53)(54). At least in response to hypoxia, the signal transduction pathway is protein kinase C dependent.…”

Lasting N-Terminal Phosphorylation of c-Jun and Activation of c-Jun N-Terminal Kinases after Neuronal Injury

“…Suppression of c-Jun expression by antisense-oligonucleotides or f unctional blockade by microinjection of antibodies protects neonatal hippocampal and sympathetic neurons from neuronal cell death in culture (Schlingensiepen et al, 1993;Estus et al, 1994;Ham et al, 1995). Enhanced c-Jun expression occurs in degenerating and apoptotic neurons after ischemia, nerve fiber transection, and UV irradiation as well as in biopsies from patients suffering from multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis (Anderson et al, 1994;Ferrer et al, 1996a,b;Martin et al, 1996).…”