Bender R A, Lauterborn J C, Gall C M, Cariaga W, Baram T Z
Department of Anatomy/Neurobiology, University of California at Irvine, Med. Sci. I, 4475, 92697-4475, USA.
Eur J Neurosci. 2001 Feb;13(4):679-86. doi: 10.1046/j.1460-9568.2001.01432.x.
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.
齿状回颗粒细胞的分化和成熟需要众多过程的协同相互作用。这些过程必须由能够整合通过多种信号通路介导的信号的蛋白质因子来调节。这种细胞间和细胞内生理刺激的整合因子包括环磷酸腺苷反应元件结合蛋白（CREB），它是一种通过磷酸化激活的亮氨酸拉链类转录因子。已知参与颗粒细胞分化的神经元活动和神经营养因子是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同基因转录中发挥作用，我们确定了未成熟大鼠海马体出生后发育过程中磷酸化（激活）CREB的时空分布。我们证明，CREB的激活局限于颗粒细胞分化的离散早期阶段。此外，CREB磷酸化发生在神经营养因子脑源性神经营因子（BDNF）和神经营养因子-3（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反应中，CREB位于神经营养因子的上游。重要的是，CREB可能是调节有助于颗粒细胞分化及其整合到齿状回网络中的基因协同转录机制的关键组成部分。
