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Regulation and transcriptional role of CRTC1 during activity in neurons


Long term memory is mediated by long-lasting forms of synaptic plasticity that require new gene transcription for their persistence. Previous work has shown that neuronal CREB-regulated transcriptional coactivator 1 (CRTC1) plays a crucial role during learning and memory by regulating activity-dependent gene expression. We have shown that CRTC1 undergoes synapse-to-nucleus translocation to regulate transcription of CREB target genes in response to neuronal activity. In this thesis, we investigate the regulation and retrograde transport of CRTC1 in neurons and examine the nuclear role of CRTC1 in activity-dependent gene transcription. Our first goal was to identify the mechanisms by which CRTC1 responds to activity. We describe key synaptic processes necessary to trigger dephosphorylation of three serine residues that are required for dynein-mediated transport of CRTC1 to the nucleus. Our second goal was to understand the role of CRCT1 as a transcriptional coactivator. We use a combination of ChIP-seq, ATAC-seq and RNA-seq to understand how CRTC1 binding to CREB and other transcription factors correlates with changes in chromatin accessibility and transcription of activity-induced genes. Finally, we summarize a series of projects that attempt to elucidate how regulation of CRTC1’s phosphorylation code may influence its function in neurons. These studies highlight the complexities of CRTC1 as an intrinsically disordered protein with 50 phosphorylated residues and a variety of potential interacting partners.

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