AP-1 Transcription Factors Mediate BDNF-Positive Feedback Loop in Cortical Neurons

Abstract

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, regulates both survival and differentiation of several neuronal populations in the nervous system during development, as well as synaptic plasticity in the adult brain. BDNF exerts its biological functions through its receptor TrkB. Although the regulation of BDNF transcription by neuronal activity has been widely studied, little is known about TrkB signaling-dependent expression of BDNF. Using rat primary cortical neuron cultures, we show that the BDNF gene is a subject to an extensive autoregulatory loop, where TrkB signaling upregulates the expression of all major BDNF transcripts, mainly through activating MAPK pathways. Investigating the mechanisms behind this autoregulation, we found that AP-1 transcription factors, comprising Jun and Fos family members, participate in the induction of BDNF exon I, III, and VI transcripts. AP-1 transcription factors directly upregulate the expression of exon I transcripts by binding two novel AP-1 cis-elements in promoter I. Moreover, our results show that the effect of AP-1 proteins on the activity of rat BDNF promoters III and VI is indirect, because AP-1 proteins were not detected to bind the respective promoter regions by chromatin immunoprecipitation (ChIP). Collectively, we describe an extensive positive feedback system in BDNF regulation, adding a new layer to the elaborate control of BDNF gene expression.

Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration

“…7a). A major target of TrkB signalling is BDNF itself, the expression of which has recently been found to be under the control of a TrkB-mediated positive feedback loop474849. Thus, if AP-2 loss indeed impairs TrkB signalling one would expect the expression of BDNF to be reduced in KO mice lacking neuronal AP-2.…”

“…7v,w). Given the positive feedback loop between TrkB signalling and BDNF expression474849, we analysed BDNF mRNA expression levels in WT and AP-2 KO neurons by qPCR (Fig. 7d).…”

“…As retrograde transport of TrkB-containing endosomes is required for neurotrophins to exert their transcriptional regulation of activity-dependent genes, most notably of BDNF (ref. 49), in the nucleus3848, the loss of neuronal complexity and subsequent neurodegeneration in AP-2 KO mice is likely the consequence of defective BDNF gene transcriptional regulation due to impaired retrograde autophagosome transport (Fig. 7a).…”

Dopamine cross‐reacts with adrenoreceptors in cortical astrocytes to induce BDNF expression, CREB signaling and morphological transformation

“…BDNF promoter constructs were generated by amplifying the corresponding sequences from rat genomic DNA using the Expand High Fidelity PCR System (Roche) and cloning into pGL4.15[luc2P/Hygro] (Promega) in front of the firefly luciferase coding sequence. Rat and human BDNF promoter IV and VI constructs have been described previously: rat IV (Koppel & Timmusk, ), human IV (Pruunsild et al, ), rat and human VI (Tuvikene, Pruunsild, Orav, Esvald, & Timmusk, ). Genome Browser coordinates for the used genomic fragments are as follows: rat IV chr3:100,786,659‐100,787,183/rn6, rat VI chr3:100,787,725‐100,788,266/rn6, human IV chr11:27,701,313‐27,701,837/hg38, human VI chr11:27,700,200‐27,700,772/hg38.…”

The Contribution of Spatial and Temporal Molecular Networks in the Induction of Long-term Memory and Its Underlying Synaptic Plasticity

“…c-Jun can associate with another transcription factor, c-Fos, to form the AP-1 transcriptional complex, which can in turn regulate the expression of several genes including those related to cell cycle progression and differentiation [19]. Intriguingly, AP-1 transcription factors are critical for positive feedback loops induced by brain derived neurotrophic factor (BDNF) in cortical neurons [22], a growth factor critical for long-lasting memory and plasticity (reviewed below). Moreover, AP-1 DNA binding activity is increased after LTP induction in the dentate gyrus [23], and a specific inhibitor of JNK phosphorylation, but not ERK1/2 or p38 MAPK phosphorylation, enhanced STM and blocked LTM for inhibitory avoidance in rats [24].…”