TORC1 Regulates Activity-Dependent CREB-Target Gene Transcription and Dendritic Growth of Developing Cortical Neurons

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.