AP-1 Transcription Factors Mediate BDNF-Positive Feedback Loop in Cortical Neurons
AP-1 Transcription Factors Mediate BDNF-Positive Feedback Loop in Cortical Neurons
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DOI：
10.1523/jneurosci.3360-15.2016
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发表时间：
2016-01
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影响因子：
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通讯作者：
Jürgen Tuvikene;P. Pruunsild;E. Orav;Eli-Eelika Esvald;T. Timmusk
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作者：
Jürgen Tuvikene;P. Pruunsild;E. Orav;Eli-Eelika Esvald;T. Timmusk
脑源性神经营养因子(BDNF)是神经营养因子家族中的一员，在发育过程中调节神经系统中几个神经元群体的存活和分化，以及成年大脑中突触的可塑性。BDNF通过其受体TrkB发挥生物学功能。尽管神经元活性对BDNF转录的调控已被广泛研究，但对TrkB信号依赖的BDNF的表达知之甚少。利用原代培养的大鼠皮质神经元，我们发现BDNF基因是一个广泛的自动调节环，其中TrkB信号主要通过激活MAPK通路上调所有主要BDNF转录本的表达。研究这种自我调节的机制，我们发现AP-1转录因子，包括Jun和Fos家族成员，参与了BDNF外显子I、III和VI转录的诱导。AP-1转录因子通过与启动子I中的两个新的AP-1顺式元件结合，直接上调外显子I转录产物的表达。此外，我们的结果表明，AP-1蛋白对大鼠脑源性神经营养因子启动子III和VI活性的影响是间接的，因为染色质免疫沉淀(ChIP)没有检测到AP-1蛋白与各自的启动子区域结合。总而言之，我们描述了一个广泛的正反馈系统来调控BDNF，为精细控制BDNF基因的表达增加了一个新的层面。在这里，我们首次表明在大鼠原代皮质神经元中，所有主要的BDNF转录本(外显子I、II、III、IV、VI和IXa转录本)的表达都对TrkB信号做出反应，并且AP-1转录因子参与了外显子I、III和VI转录本的诱导。此外，我们还描述了BDNF启动子I中两个新的AP-1顺式元件，它们负责激活启动子以响应TrkB信号。我们的结果表明，存在一个正反馈环路，以获得神经元中各种TrkB信号依赖的生理结果所需的足够的BDNF水平。
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. SIGNIFICANCE STATEMENT Here, we show for the first time that in rat primary cortical neurons the expression of all major BDNF transcripts (exon I, II, III, IV, VI, and IXa transcripts) is upregulated in response to TrkB signaling, and that AP-1 transcription factors participate in the induction of exon I, III, and VI transcripts. Moreover, we have described two novel functional AP-1 cis-elements in BDNF promoter I, responsible for the activation of the promoter in response to TrkB signaling. Our results indicate the existence of a positive feedback loop for obtaining sufficient BDNF levels necessary for various TrkB signaling-dependent physiological outcomes in neurons.