TORC1 Regulates Activity-Dependent CREB-Target Gene Transcription and Dendritic Growth of Developing Cortical Neurons
TORC1 Regulates Activity-Dependent CREB-Target Gene Transcription and Dendritic Growth of Developing Cortical Neurons
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DOI：
10.1523/jneurosci.2296-08.2009
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发表时间：
2009-02-25
影响因子：
5.3
通讯作者：
Xiong, Zhi-Qi
中科院分区：
文献类型：
--
作者：
Li, Shuai;Zhang, Chi;Xiong, Zhi-Qi
CREB靶基因在神经元兴奋过程中的转录对神经元发育和功能的许多方面都很重要，包括树突形态发生。然而，在树突发育过程中调节cAMP反应元件结合蛋白（CREB）介导的基因转录的信号事件还没有很好地理解。在这里，我们报告的CREB辅激活TORC 1（调节CREB 1的换能器）是必需的活性依赖性CREB靶基因表达和树突生长发育皮层神经元。通过电压门控钙通道的Ca 2+内流诱导TORC 1去磷酸化并以钙调神经磷酸酶依赖的方式易位到细胞核中。TORC 1的核积累启动CREB靶基因的表达，包括盐诱导激酶1（SIK 1）。在持续去极化的反应，从头SIK 1蛋白反过来促进TORC 1磷酸化和随之而来的核定位TORC 1耗尽。因此，SIK 1诱导似乎作为一种负反馈信号，防止持久的CREB/TORC 1依赖性转录在面对持久的神经元活动。过表达野生型TORC 1促进基础以及活性诱导的树突状细胞生长，而表达显性负性形式的TORC 1或下调TORC 1抑制活性依赖性树突状细胞生长在体外和体内。总之，这些结果表明，在发育中的皮层神经元的神经元活性依赖性树突状细胞的生长依赖于瞬时TORC 1介导的CREB靶基因转录。
CREB-target gene transcription during neuronal excitation is important for many aspects of neuronal development and function, including dendrite morphogenesis. However, the signaling events that regulate cAMP response element-binding protein (CREB)-mediated gene transcription during dendritic development are not well understood. Herein we report that the CREB coactivator TORC1 (transducer of regulated CREB 1) is required for activity-dependent CREB-target gene expression and dendrite growth in developing cortical neurons. Ca2+ influx via voltage-gated calcium channels induced TORC1 dephosphorylation and translocation into the nucleus in a calcineurin-dependent manner. Nuclear accumulation of TORC1 initiated the expression of CREB-target genes, including salt-inducible kinase 1 (SIK1). In response of persistent depolarization, de novo SIK1 protein in turn promoted TORC1 phosphorylation and consequent depletion of nucleus-localized TORC1. SIK1 induction thus appears to act as a negative feedback signal that prevents persistent CREB/TORC1-dependent transcription in the face of long-lasting neuronal activity. Overexpressing wild type TORC1 promoted basal as well as activity-induced dendritic growth, whereas expressing a dominant-negative form of TORC1 or downregulating TORC1 inhibited activity-dependent dendritic growth in vitro and in vivo. Together, these results suggest that neuronal activity-dependent dendritic growth in developing cortical neurons relies on transient TORC1-mediated CREB-target gene transcription.