A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity.
A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity.
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DOI：
10.1016/j.biopsych.2011.11.030
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发表时间：
2012-04-01
影响因子：
10.6
通讯作者：
MacKenzie, Alasdair
中科院分区：
文献类型：
--
作者：
Hing, Benjamin;Davidson, Scott;Lear, Marrisa;Breen, Gerome;Quinn, John;McGuffin, Peter;MacKenzie, Alasdair
关键词：
脑源性神经营养因子（BDNF）表达的变化与情绪障碍和认知功能障碍有关。 BDNF 过度表达或表达不足的转基因模型在认知和情绪方面表现出类似的缺陷。我们探讨了这样的假设：BDNF 表达是通过平衡 BDNF 启动子 IV (BP4) 的活性与含有与认知功能障碍和情绪障碍相关的多态性的负调控区来控制的。我们使用比较基因组学、转基因小鼠生产以及用荧光素酶报告基因和信号转导激动剂治疗对原代神经元进行磁转染来鉴定控制 BP4 活性的新型多态性顺式调节区域。我们发现 BP4 在海马体、皮质和杏仁核中活跃，并对氯化钾、氯化锂和蛋白激酶 C 激动剂等刺激反应强烈。我们还鉴定了 BP4 的 21 kilobase 5' 高度保守序列，我们称之为 BE5.2，其中包含 rs12273363，这是一种与 BDNF 表达减少、情绪障碍和认知能力下降相关的多态性。 BE5.2调节BP4对不同刺激的反应能力。有趣的是，与更罕见的疾病相关的等位基因 BE5.2(C) 比更常见的 BE5.2(T) 等位基因对 BP4 活性具有更强的抑制作用。这项研究表明，与情绪障碍相关的 rs12273363 的 C 等位基因在细胞去极化或蛋白激酶 A 和蛋白激酶 C 途径的组合活性后以等位基因特异性方式调节 BP4 活性。讨论了这些发现与 BDNF 错误表达在情绪障碍和认知能力下降中的作用的相关性。
Changes in brain derived neurotrophic factor (BDNF) expression have been associated with mood disorders and cognitive dysfunction. Transgenic models that overexpress or underexpress BDNF demonstrate similar deficits in cognition and mood. We explored the hypothesis that BDNF expression is controlled by balancing the activity of BDNF promoter IV (BP4) with a negative regulatory region containing a polymorphism associated with cognitive dysfunction and mood disorders. We used comparative genomics, transgenic mouse production, and magnetofection of primary neurons with luciferase reporters and signal transduction agonist treatments to identify novel polymorphic cis-regulatory regions that control BP4 activity. We show that BP4 is active in the hippocampus, the cortex, and the amygdala and responds strongly to stimuli such as potassium chloride, lithium chloride, and protein kinase C agonists. We also identified a highly conserved sequence 21 kilobase 5' of BP4 that we called BE5.2, which contains rs12273363, a polymorphism associated with decreased BDNF expression, mood disorders, and cognitive decline. BE5.2 modulated the ability of BP4 to respond to different stimuli. Intriguingly, the rarer disease associated allele, BE5.2(C), acted as a significantly stronger repressor of BP4 activity than the more common BE5.2(T) allele. This study shows that the C allele of rs12273363, which is associated with mood disorder, modulates BP4 activity in an allele-specific manner following cell depolarization or the combined activity of protein kinase A and protein kinase C pathways. The relevance of these findings to the role of BDNF misexpression in mood disorders and cognitive decline is discussed.
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影响因子：
82.9
作者：
Eriksson, PS;Perfilieva, E;Gage, FH
通讯作者：
Gage, FH
影响因子：
7.6
作者：
Bearden, Carrie E.;Thompson, Paul M.;Soares, Jair C.
通讯作者：
Soares, Jair C.
影响因子：
2.5
作者：
Chen, HX;Roper, SN
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Roper, SN
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3.3
作者：
Dwivedi, Y.;Rizavi, H. S.;Pandey, G. N.
通讯作者：
Pandey, G. N.
影响因子：
4.7
作者：
Bearden CE;Thompson PM;Avedissian C;Klunder AD;Nicoletti M;Dierschke N;Brambilla P;Soares JC
通讯作者：
Soares JC