BDNF-promoted increases in proximal dendrites occur via CREB-dependent transcriptional regulation of cypin.
BDNF-promoted increases in proximal dendrites occur via CREB-dependent transcriptional regulation of cypin.
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DOI：
10.1523/jneurosci.6785-10.2011
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发表时间：
2011-06-29
期刊：
影响因子：
--
通讯作者：
Firestein BL
中科院分区：
文献类型：
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作者：
Kwon M;Fernández JR;Zegarek GF;Lo SB;Firestein BL
树突分支和形态学的改变存在于许多神经退行性疾病中。这些变异破坏突触后传递并影响神经元通信。因此，重要的是要了解调节树突状细胞发生的分子机制，以及它们在疾病状态下如何出错。以前，我们的实验室表明，cypin，哺乳动物鸟嘌呤脱氨酶，增加树突数时，过度表达和减少树突数时，敲在培养的海马神经元。在这里，我们报告说，暴露于脑源性神经营养因子（BDNF），树突树枝化的重要介质，72小时，但不是24小时或更短，增加cypin mRNA和蛋白质水平在大鼠海马神经元。BDNF通过cypin信号调节树突数量，因为敲低cypin阻断了BDNF的作用。此外，BDNF通过丝裂原活化蛋白激酶（MAPK）和转录依赖性信号通路增加cypin水平。此外，cypin启动子区含有保守的环腺苷酸反应元件（cyclic adenosine 3 '，5'-monophosphate，cAMP response element-binding protein，CREB）。此外，暴露于BDNF的神经元增加CREB结合到cypin启动子，并与这些数据一致，CREB的显性负性形式的表达阻断了BDNF促进的cypin蛋白水平和近端树突分支的增加。总之，这些研究表明，BDNF通过激活CREB增加神经元cypin表达，增加cypin转录导致蛋白质表达增加，从而确定了BDNF形成树突网络的新途径。
Alterations in dendrite branching and morphology are present in many neurodegenerative diseases. These variations disrupt postsynaptic transmission and affect neuronal communication. Thus, it is important to understand the molecular mechanisms that regulate dendritogenesis and how they go awry during disease states. Previously, our laboratory showed that cypin, a mammalian guanine deaminase, increases dendrite number when overexpressed and decreases dendrite number when knocked down in cultured hippocampal neurons. Here, we report that exposure to brain-derived neurotrophic factor (BDNF), an important mediator of dendrite arborization, for 72 hours but not for 24 hours or less, increases cypin mRNA and protein levels in rat hippocampal neurons. BDNF signals through cypin to regulate dendrite number since knocking down cypin blocks the effects of BDNF. Furthermore, BDNF increases cypin levels via mitogen-activated protein kinase (MAPK) and transcription-dependent signaling pathways. Moreover, the cypin promoter region contains putative conserved cyclic adenosine 3’,5’-monophosphate (cAMP) response element (CRE) regions, which we found can be recognized and activated by cAMP response element-binding protein (CREB). In addition, exposure of the neurons to BDNF increased CREB binding to the cypin promoter and, in line with these data, expression of a dominant negative form of CREB blocked BDNF-promoted increases in cypin protein levels and proximal dendrite branches. Taken together, these studies suggest that BDNF increases neuronal cypin expression by the activation of CREB, increasing cypin transcription leading to increased protein expression, thus identifying a novel pathway by which BDNF shapes the dendrite network.