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TORC1 regulates activity-dependent CREB-target gene transcription and dendritic growth of developing cortical neurons.

Authors
  • Li, Shuai
  • Zhang, Chi
  • Takemori, Hiroshi
  • Zhou, Yang
  • Xiong, Zhi-Qi
Type
Published Article
Journal
Journal of Neuroscience
Publisher
Society for Neuroscience
Publication Date
Feb 25, 2009
Volume
29
Issue
8
Pages
2334–2343
Identifiers
DOI: 10.1523/JNEUROSCI.2296-08.2009
PMID: 19244510
Source
Medline
License
Unknown

Abstract

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. Ca(2+) 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.

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