Evidence for a non-canonical JAK/STAT signaling pathway in the synthesis of the brain’s major ion channels and neurotransmitter receptors

Abstract

Background Brain-derived neurotrophic factor (BDNF) is a major signaling molecule that the brain uses to control a vast network of intracellular cascades fundamental to properties of learning and memory, and cognition. While much is known about BDNF signaling in the healthy nervous system where it controls the mitogen activated protein kinase (MAPK) and cyclic-AMP pathways, less is known about its role in multiple brain disorders where it contributes to the dysregulated neuroplasticity seen in epilepsy and traumatic brain injury (TBI). We previously found that neurons respond to prolonged BDNF exposure (both in vivo (in models of epilepsy and TBI) and in vitro (in BDNF treated primary neuronal cultures)) by activating the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway. This pathway is best known for its association with inflammatory cytokines in non-neuronal cells. Results Here, using deep RNA-sequencing of neurons exposed to BDNF in the presence and absence of well characterized JAK/STAT inhibitors, and without non-neuronal cells, we determine the BDNF transcriptome that is specifically regulated by agents that inhibit JAK/STAT signaling. Surprisingly, the BDNF-induced JAK/STAT transcriptome contains ion channels and neurotransmitter receptors coming from all the major classes expressed in the brain, along with key modulators of synaptic plasticity, neurogenesis, and axonal remodeling. Analysis of this dataset has revealed a unique non-canonical mechanism of JAK/STATs in neurons as differential gene expression mediated by STAT3 is not solely dependent upon phosphorylation at residue 705 and may involve a BDNF-induced interaction of STAT3 with Heterochromatin Protein 1 alpha (HP1α). Conclusions These findings suggest that the neuronal BDNF-induced JAK/STAT pathway involves more than STAT3 phosphorylation at 705, providing the first evidence for a non-canonical mechanism that may involve HP1α. Our analysis reveals that JAK/STAT signaling regulates many of the genes associated with epilepsy syndromes where BDNF levels are markedly elevated. Uncovering the mechanism of this novel form of BDNF signaling in the brain may provide a new direction for epilepsy therapeutics and open a window into the complex mechanisms of STAT3 transcriptional regulation in neurological disease. Electronic supplementary material The online version of this article (10.1186/s12864-019-6033-2) contains supplementary material, which is available to authorized users.

STAT3–BDNF–TrkB signalling promotes alveolar epithelial regeneration after lung injury

“…It is possible that, using different selection criteria, we would have identified additional candidates. Although BDNF stands for 'brain-derived neurotrophic factor' , the regulation of Bdnf by STAT3 has previously been reported in multiple cell types [53][54][55][56] . While BDNF has been detected in lung cancer lines 68 , it has not previously been implicated in alveolar epithelial regeneration.…”

“…4d). We identified Bdnf 52 as being the only bona fide STAT3 target gene [53][54][55][56] whose chromatin is newly accessible after lung injury ( Fig. 4d and Supplementary Table 1) and whose expression is restricted to the regenerating population of cells.…”

Ablation of STAT3 in Purkinje Cells Reorganizes Cerebellar Synaptic Plasticity in Long-Term Fear Memory Network

“…For example, STAT3 regulates long-term depression (LTD) dependent on N-methyl-D-aspartate receptors (NMDA-Rs) in the hippocampus in noncanonical way (Nicolas et al, 2012). Genomics research supports the concept of noncanonical JAK/STAT signaling pathway in the synthesis of the brain's major ion channels and neurotransmitters (Hixson et al, 2019). However, canonical JAK/STAT signaling is also involved in long-term depression at hippocampal temporoammonic-CA1 synapses (McGregor et al, 2017).…”

Tittle Exploring the Mechanism of Resveratrol on Traumatic Brain Injury by Network Pharmacology and Molecular Docking

“…IGF1 can promote the growth and differentiation of neurons and plays an important role in repair and nerve regeneration after central nervous system injury [37] . TNF is an important immunomodulatory and in ammatory factor involved in the in ammatory process that occurs after TBI [38] . TP53 plays a regulatory role in controlling the cell cycle and initiating cell apoptosis and is also involved in DNA damage repair.…”