Enhanced CREB phosphorylation in immature dentate gyrus granule cells precedes neurotrophin expression and indicates a specific role of CREB in granule cell differentiation
Enhanced CREB phosphorylation in immature dentate gyrus granule cells precedes neurotrophin expression and indicates a specific role of CREB in granule cell differentiation
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DOI：
10.1046/j.1460-9568.2001.01432.x
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发表时间：
2001-02-01
影响因子：
3.4
通讯作者：
Baram, TZ
中科院分区：
文献类型：
--
作者：
Bender, RA;Lauterborn, JC;Baram, TZ
齿状回颗粒细胞的分化和成熟需要多个过程的协调相互作用。这些必须由能够整合各种信号通路介导的信号的蛋白质因子调节。细胞间和细胞内生理刺激的整合者包括camp反应元件结合蛋白（CREB），这是一种通过磷酸化激活的亮氨酸拉链类转录因子。神经元活动和神经营养因子参与颗粒细胞分化，是CREB功能的主要生理调节因子。为了研究CREB是否可能在颗粒细胞分化过程中调控协调基因转录中发挥作用，我们确定了未成熟大鼠海马在出生后发育过程中磷酸化（激活）CREB的时空分布。我们证明CREB激活仅限于离散的颗粒细胞分化的早期阶段。此外，CREB磷酸化发生在神经营养因子BDNF和NT-3表达之前。这些数据表明，在颗粒细胞成熟过程中连接CREB和神经营养因子的信号转导级联中，CREB位于神经营养因子的上游。重要的是，CREB可能是调节基因协调转录机制的关键组成部分，这些基因有助于颗粒细胞的分化并整合到齿状回网络中。
Differentiation and maturation of dentate gyrus granule cells requires coordinated interactions of numerous processes. These must be regulated by protein factors capable of integrating signals mediated through diverse signalling pathways. Such integrators of inter and intracellular physiological stimuli include the cAMP-response element binding protein (CREB), a leucine-zipper class transcription factor that is activated through phosphorylation. Neuronal activity and neurotrophic factors, known to be involved in granule cell differentiation, are major physiologic regulators of CREB function. To examine whether CREB may play a role in governing coordinated gene transcription during granule cell differentiation, we determined the spatial and temporal profiles of phosphorylated (activated) CREB throughout postnatal development in immature rat hippocampus. We demonstrate that CREB activation is confined to discrete, early stages of granule cell differentiation. In addition, CREB phosphorylation occurs prior to expression of the neurotrophins BDNF and NT-3. These data indicate that in a signal transduction cascade connecting CREB and neurotrophins in the process of granule cell maturation, CREB is located upstream of neurotrophins. Importantly, CREB may be a critical component of the machinery regulating the coordinated transcription of genes contributing to the differentiation of granule cells and their integration into the dentate gyrus network.