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The Class I E3 Ubiquitin Ligase TRIM67 Modulates Brain Development and Behavior

Nicholas P. Boyer, Caroline Monkiewicz, Sheryl S. Moy, View ORCID ProfileStephanie L. Gupton
doi: https://doi.org/10.1101/241331
Nicholas P. Boyer
1Curriculum in Neurobiology, University of North Carolina at Chapel Hill
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Caroline Monkiewicz
2Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill
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Sheryl S. Moy
3Department of Psychiatry, University of North Carolina at Chapel Hill
4Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill
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Stephanie L. Gupton
2Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill
5Neuroscience Center, University of North Carolina at Chapel Hill
6Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill 111 Mason Farm Road, Chapel Hill, North Carolina 27599
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ABSTRACT

Specific class I members of the TRIM family of E3 ubiquitin ligases have been implicated in neuronal development from invertebrates to mammals. The single invertebrate class I TRIM and mammalian TRIM9 regulate axon branching and guidance in response to the axon guidance cue netrin-1, whereas mammalian TRIM46 establishes the axon initial segment. In humans, mutations in TRIM1 and TRIM18 are implicated in Optiz Syndrome, characterized by midline defects and often mild intellectual disability. TRIM67 is the most evolutionarily conserved vertebrate class I TRIM, yet is the least studied. Here we show that TRIM67 interacts with both its closest paralog TRIM9 and the netrin receptor DCC, and is differentially enriched in specific brain regions at specific developmental points. We describe the anatomical and behavioral consequences of deletion of murine Trim67. While viable, mice lacking Trim67 display severe impairments in spatial memory, cognitive flexibility, social novelty preference, muscle function and sensorimotor gating. Additionally, they exhibit abnormal anatomy of several brain regions, including the hippocampus, striatum and thalamus, as well as the corpus callosum. This study demonstrates the necessity for TRIM67 in appropriate brain development and function.

SIGNIFICANCE STATEMENT As a family, class I TRIM E3 ubiquitin ligases play important roles in neuronal development and function, potentially cooperatively. TRIM67 is the most evolutionarily conserved class I TRIM and is developmentally regulated and brain-enriched. Deletion of murine Trim67 results in malformations of a subset subcortical brain regions and of cortical and subcortical myelinated fiber tracts, as well as deficits in spatial memory, motor function, sociability and sensorimotor gating. We conclude that TRIM67 is critical for appropriate brain development and behavior, potentially downstream of the axon guidance cue netrin, and in cooperation with class I TRIM9.

Footnotes

  • sgupton{at}email.unc.edu

  • The authors declare no competing financial interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 30, 2017.
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The Class I E3 Ubiquitin Ligase TRIM67 Modulates Brain Development and Behavior
Nicholas P. Boyer, Caroline Monkiewicz, Sheryl S. Moy, Stephanie L. Gupton
bioRxiv 241331; doi: https://doi.org/10.1101/241331
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The Class I E3 Ubiquitin Ligase TRIM67 Modulates Brain Development and Behavior
Nicholas P. Boyer, Caroline Monkiewicz, Sheryl S. Moy, Stephanie L. Gupton
bioRxiv 241331; doi: https://doi.org/10.1101/241331

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