The formation of a dendritic arbor, a critical step in the establishment of neuronal connectivity, is regulated by neuronal activity. Episodes of neuronal activity during development lead to Ca²⁺-dependent gene expression and long-lasting changes in dendrite morphology. The transcription factor cAMP-response element-binding protein (CREB) plays important roles in this process, but how cytoplasmic Ca²⁺ signaling propagates to the nucleus for gene transcription is not clear.

Published in the February 25^th issue of the Journal of Neuroscience, work from the Laboratory of Neurobiology of Disease, mainly carried out by graduate student Shuai Li under the supervision of Dr. Zhi-Qi Xiong, reported that the CREB co-activator TORC1 regulates activity-dependent CREBa€“target gene transcription and dendritic growth in developing cortical neurons. The authors demonstrated that 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 nuclear-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 wildtype TORC1 promoted basal as well as activity-induced dendritic growth, whereas expressing a dominant-negative form of TORC1 or down-regulating TORC1 inhibited activity-dependent dendritic growth in vitro and in vivo. These results suggest that activity-dependent dendritic growth in developing cortical neurons relies on transient TORC1-mediated CREB-target gene transcription.

This work was supported by the Ministry of Science and Technology, the National Science Foundation of China and the Chinese Academy of Sciences.