Cytoplasmic Polyadenylation Element-Binding Protein Regulates Neurotrophin-3-Dependent β-Catenin mRNA Translation in Developing Hippocampal Neurons
Cytoplasmic Polyadenylation Element-Binding Protein Regulates Neurotrophin-3-Dependent β-Catenin mRNA Translation in Developing Hippocampal Neurons
复制标题
DOI：
10.1523/jneurosci.2910-08.2009
复制
发表时间：
2009-10-28
影响因子：
5.3
通讯作者：
Wells, David G.
中科院分区：
文献类型：
--
作者：
Kundel, Mitchell;Jones, Kendrick J.;Wells, David G.
神经元形态发生，即神经元过程的生长和树枝化，是大脑发育的重要组成部分。先前已经描述了调节神经元形态的两个重要但看似不同的成分。在海马体中，神经营养蛋白，特别是脑源性神经营养因子 (BDNF) 和神经营养蛋白-3 (NT3)，可增强细胞生长和分支，而活动诱导的分支则依赖于细胞内 β-连环蛋白。我们现在描述了 NT3 刺激和发育神经元中 β-连环蛋白增加之间的分子联系，并证明该过程是 NT3 介导的过程分支增加所必需的。在这里，我们发现在 NT3 刺激后，β-连环蛋白特别是在生长锥中迅速增加。 β-连环蛋白的这种增加依赖于蛋白质合成，并且需要细胞质多腺苷酸化元件结合蛋白-1 (CPEB1) 的活性，CPEB1 是一种调节 mRNA 翻译的 mRNA 结合蛋白。我们发现 CPEB1 蛋白以 CPE 依赖性方式结合 β-连环蛋白 mRNA，并且两者都定位于发育中的海马神经元的生长锥。当 CPEB1 功能受到抑制时，NT3 介导的 β-连环蛋白快速增加和过程分支都会消失。此外，NT3 介导的生长锥中 β-连环蛋白的增加取决于内部钙和 CaMKII（钙/钙调蛋白依赖性激酶 II）的活性。总之，这些结果表明 CPEB1 调节神经元中 β-连环蛋白的合成，并可能有助于神经元形态发生。
Neuronal morphogenesis, the growth and arborization of neuronal processes, is an essential component of brain development. Two important but seemingly disparate components regulating neuronal morphology have previously been described. In the hippocampus, neurotrophins, particularly brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3), act to enhance cell growth and branching, while activity-induced branching was shown to be dependent upon intracellular beta-catenin. We now describe a molecular link between NT3 stimulation and beta-catenin increase in developing neurons and demonstrate that this process is required for the NT3-mediated increase in process branching. Here, we show that beta-catenin is rapidly increased specifically in growth cones following NT3 stimulation. This increase in beta-catenin is protein synthesis dependent and requires the activity of cytoplasmic polyadenylation element-binding protein-1 (CPEB1), an mRNA-binding protein that regulates mRNA translation. We find that CPEB1 protein binds beta-catenin mRNA in a CPE-dependent manner and that both localize to growth cones of developing hippocampal neurons. Both the NT3-mediated rapid increase in beta-catenin and process branching are abolished when CPEB1 function is inhibited. In addition, the NT3-mediated increase in beta-catenin in growth cones is dependent upon internal calcium and the activity of CaMKII (calcium/calmodulin-dependent kinase II). Together, these results suggest that CPEB1 regulates beta-catenin synthesis in neurons and may contribute to neuronal morphogenesis.