AUTHOR=Ch'ng Toh Hean , DeSalvo Martina , Lin Peter , Vashisht Ajay , Wohlschlegel James , Martin Kelsey TITLE=Cell biological mechanisms of activity-dependent synapse to nucleus translocation of CRTC1 in neurons JOURNAL=Frontiers in Molecular Neuroscience VOLUME=8 YEAR=2015 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2015.00048 DOI=10.3389/fnmol.2015.00048 ISSN=1662-5099 ABSTRACT=

Previous studies have revealed a critical role for CREB-regulated transcriptional coactivator (CRTC1) in regulating neuronal gene expression during learning and memory. CRTC1 localizes to synapses but undergoes activity-dependent nuclear translocation to regulate the transcription of CREB target genes. Here we investigate the long-distance retrograde transport of CRTC1 in hippocampal neurons. We show that local elevations in calcium, triggered by activation of glutamate receptors and L-type voltage-gated calcium channels, initiate active, dynein-mediated retrograde transport of CRTC1 along microtubules. We identify a nuclear localization signal within CRTC1, and characterize three conserved serine residues whose dephosphorylation is required for nuclear import. Domain analysis reveals that the amino-terminal third of CRTC1 contains all of the signals required for regulated nucleocytoplasmic trafficking. We fuse this region to Dendra2 to generate a reporter construct and perform live-cell imaging coupled with local uncaging of glutamate and photoconversion to characterize the dynamics of stimulus-induced retrograde transport and nuclear accumulation.