Synaptogenesis Regulates Axotomy-Induced Activation of c-Jun-Activator Protein-1 Transcription

Abstract

The activator protein-1 (AP1) transcription complex remains active for long periods after axotomy, but its activity diminishes during target contact. This raises the possibility that the function of this complex is regulated by the synaptic connections. Using Aplysia californica, we found that crushing peripheral nerves in vivo enhanced AP1 binding in the sensory neurons that lasted for weeks and then declined as regeneration was completed. The AP1 complex in Aplysia is a c-Jun homodimer. Its activation, after axotomy, is mediated by Aplysia c-Jun-N-terminal kinase (apJNK), which enters the nucleus of sensory neurons and phosphorylates c-Jun at Ser-73 (p73-c-Jun). Active AP1 in the sensory neurons did not mediate apoptosis and was not involved in the appearance of the long-term hyperexcitability that develops in these cells after axotomy, and blocking the activation of apJNK in vitro did not influence neurite outgrowth. In contrast, the levels of activated apJNK and p73-c-Jun declined markedly when sensory neurons formed synapses with motor neuron L7 in vitro. Furthermore, inhibiting the pathway accelerated synaptogenesis between sensory neurons and L7. These data suggest that positive and negative modulation of the JNK-c-Jun-AP1 pathway functions in alerting the nucleus to the loss and gain of synapses, respectively.

Identification of candidate transcriptional modulators involved in successful regeneration after nerve injury

“…However, its prolonged up‐regulation does not suggest a role in the initiation of neurite outgrowth. Recent findings indicate that cJun activation is associated with the injury‐induced loss of synaptic contact rather than with neurite extension (Sung et al ., 2006). In conclusion, our paradigm successfully identified transcriptional modulators known to enhance neurite outgrowth and/or regeneration.…”

A novel inhibitor of active protein kinase G attenuates chronic inflammatory and osteoarthritic pain

“…42–44 Regardless, N46 will be effective in either circumstance because it both blocks the activation of PKG-1α and inhibits the already activated kinase.…”

General Anesthesia Causes Epigenetic Histone Modulation of c-Fos and Brain-derived Neurotrophic Factor, Target Genes Important for Neuronal Development in the Immature Rat Hippocampus

“…Despite the rapid (and in several models, transient) epigenetic changes in c-Fos and BDNF promotors, these modulations have long-lasting influence via the activator protein (AP)-1 complex and AP-1 binding region on promoters of numerous later response genes that participate in processes crucial for neuronal development and survival. 55 …”