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bioRxiv · 10.1101/2023.12.31.573790

The E3 ubiquitin ligase TRIM9 regulates synaptic function and actin dynamics

McCormick, L. E.·Evans, E. B.·Barker, N. K.·Herring, L. E.·Gupton, S. L.
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Abstract

During neuronal development, dynamic filopodia emerge from dendrites and mature into functional dendritic spines during synaptogenesis. Dendritic filopodia and spines respond to extracellular cues, influencing dendritic spine shape and size as well as synaptic function. Previously, the E3 ubiquitin ligase TRIM9 was shown to regulate filopodia in early stages of neuronal development, including netrin-1 dependent axon guidance and branching. Here we demonstrate TRIM9 also localizes to dendritic filopodia and spines of murine cortical and hippocampal neurons during synaptogenesis and is required for synaptic responses to netrin. In particular, TRIM9 is enriched in the post-synaptic density (PSD) within dendritic spines and loss of Trim9 alters the PSD proteome, including the actin cytoskeleton landscape. While netrin exposure induces accumulation of the Arp2/3 complex and filamentous actin in dendritic spine heads, this response is disrupted by genetic deletion of Trim9. In addition, we document changes in the synaptic receptors associated with loss of Trim9. These defects converge on a loss of netrindependent increases in neuronal firing rates, indicating TRIM9 is required downstream of synaptic netrin-1 signaling. We propose TRIM9 regulates cytoskeletal dynamics in dendritic spines and is required for the proper response to synaptic stimuli.

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McCormick, L. E., Evans, E. B., Barker, N. K., Herring, L. E., Gupton, S. L.. 2024-01-01. The E3 ubiquitin ligase TRIM9 regulates synaptic function and actin dynamics. https://doi.org/10.1101/2023.12.31.573790

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