RNF8/UBC13 ubiquitin signaling suppresses synapse formation in the mammalian brain

Although ubiquitin ligases have been implicated in autism, their roles and mechanisms in brain development remain incompletely understood. Here, we report that in vivo knockdown or conditional knockout of the autism-linked ubiquitin ligase RNF8 or associated ubiquitin-conjugating enzyme UBC13 in rod...

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Bibliographic Details
Published in:Nature communications 2017-11, Vol.8 (1), p.1271-15, Article 1271
Main Authors: Valnegri, Pamela, Huang, Ju, Yamada, Tomoko, Yang, Yue, Mejia, Luis A., Cho, Ha Y., Oldenborg, Anna, Bonni, Azad
Format: Article
Language:English
Subjects:
631/337/474/2073
631/378/2571/2577
631/378/340
Autism
Brain
Cerebellum
Cytoplasm
Differentiation
Enzymes
Granular materials
Granule cells
Humanities and Social Sciences
multidisciplinary
Neural networks
Neurons
Presynapse
Proteins
Proteomics
Rodents
Science
Science (multidisciplinary)
Signaling
Synapses
Synaptogenesis
Ubiquitin
Ubiquitin-conjugating enzyme
Ubiquitin-protein ligase
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Summary:Although ubiquitin ligases have been implicated in autism, their roles and mechanisms in brain development remain incompletely understood. Here, we report that in vivo knockdown or conditional knockout of the autism-linked ubiquitin ligase RNF8 or associated ubiquitin-conjugating enzyme UBC13 in rodent cerebellar granule neurons robustly increases the number of parallel fiber presynaptic boutons and functional parallel fiber/Purkinje cell synapses. In contrast to the role of nuclear RNF8 in proliferating cells, RNF8 operates in the cytoplasm in neurons to suppress synapse differentiation in vivo. Proteomics analyses reveal that neuronal RNF8 interacts with the HECT domain protein HERC2 and scaffold protein NEURL4, and knockdown of HERC2 or NEURL4 phenocopies the inhibition of RNF8/UBC13 signaling on synapse differentiation. In behavior analyses, granule neuron-specific knockout of RNF8 or UBC13 impairs cerebellar-dependent learning. Our study defines RNF8 and UBC13 as components of a novel cytoplasmic ubiquitin-signaling network that suppresses synapse formation in the brain. Ubiquitin ligases play critical roles in neuronal connectivity in the brain. Here, Valnegri and colleagues show that ubiquitin ligase RNF8 and ubiquitin-conjugating enzyme UBC13 regulate synapse number in cerebellar granule neurons and rodent cerebellar learning.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-017-01333-6