title: Cell biological mechanisms of activity-dependent synapse to nucleus translocation of CRTC1 in neurons.
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.
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore ; School of Biological Sciences, Nanyang Technological University Singapore, Singapore.
authors.forename: Toh Hean
authors.initials: TH
authors.lastname: Ch'ng
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles Los Angeles, CA, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: DeSalvo
authors.affiliation: Department of Neurology and Neuroscience, Stanford University Palo Alto, CA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Lin
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles Los Angeles, CA, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Vashisht
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles Los Angeles, CA, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Wohlschlegel
authors.affiliation: Department of Biological Chemistry, University of California, Los Angeles Los Angeles, CA, USA ; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles Los Angeles, CA, USA.
authors.forename: Kelsey C
authors.initials: KC
authors.lastname: Martin
keywords: CREB; CRTC1; active transport; learning and memory; synapse to nucleus signaling; synaptic plasticity; transcription-dependent plasticity