Picower Special Seminar with Ezgi Hacisuleyman, PhD

Monday, February 27 | Singleton Auditorium (46-3002)

Dissecting Synaptic RNA Regulation in Neuronal Homeostasis and Disease

Learning and memory require activity-induced changes in local synaptic mRNA translation, but which mRNAs are involved and how they are regulated are unclear. We combined proximity labeling with CLIP, ribosome profiling, and mass-spectrometry to monitor the impact of depolarization on dendritic biology. Dynamically regulated RNAs rapidly generate dendritic proteins with roles in metabolism and synaptic signaling. Unexpectedly, depolarization leads to enhanced upstream open reading frame (uORF) translation, eIF4G2 recruitment, and increased translation in a functionally coherent set of dendritic transcripts highly enriched in mitochondrial genes. Activity-dependent translational control is conferred by 5’UTRs, and dendritic eIF4G2 binding and uORF translation are necessary and sufficient to mediate this regulation, driving changes in dendritic mitochondrial function. Our studies uncover an unanticipated mechanism by which activity-dependent uORF translational control by eIF4G2 couples synaptic activity to local dendritic remodeling and energy homeostasis. In my independent research program, I will build on the methodologies that I developed and the biology that I uncovered during my postdoctoral studies and integrate mechanistic molecular and cell biology tools with in vivo approaches to understand subcellular post-transcriptional and translational regulation in neurons and its implications in neurological disease.