RRC ID 51380
Author Opperman KJ, Mulcahy B, Giles AC, Risley MG, Birnbaum RL, Tulgren ED, Dawson-Scully K, Zhen M, Grill B.
Title The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development.
Journal Cell Rep
Abstract Genetic changes in the HECT ubiquitin ligase HUWE1 are associated with intellectual disability, but it remains unknown whether HUWE1 functions in post-mitotic neurons to affect circuit function. Using genetics, pharmacology, and electrophysiology, we show that EEL-1, the HUWE1 ortholog in C. elegans, preferentially regulates GABAergic presynaptic transmission. Decreasing or increasing EEL-1 function alters GABAergic transmission and the excitatory/inhibitory (E/I) balance in the worm motor circuit, which leads to impaired locomotion and increased sensitivity to electroshock. Furthermore, multiple mutations associated with intellectual disability impair EEL-1 function. Although synaptic transmission defects did not result from abnormal synapse formation, sensitizing genetic backgrounds revealed that EEL-1 functions in the same pathway as the RING family ubiquitin ligase RPM-1 to regulate synapse formation and axon termination. These findings from a simple model circuit provide insight into the molecular mechanisms required to obtain E/I balance and could have implications for the link between HUWE1 and intellectual disability.
Volume 19(4)
Pages 822-835
Published 2017-4-25
DOI 10.1016/j.celrep.2017.04.003
PII S2211-1247(17)30462-X
PMID 28445732
PMC PMC5475272
MeSH Aldicarb / toxicity Animals Animals, Genetically Modified / metabolism Axons / metabolism Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / antagonists & inhibitors Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Electroshock GABAergic Neurons / metabolism* Guanine Nucleotide Exchange Factors / genetics Guanine Nucleotide Exchange Factors / metabolism Hypersensitivity / etiology Locomotion / drug effects Mutagenesis, Site-Directed Presynaptic Terminals / metabolism RNA Interference Signal Transduction Synapses / metabolism Synaptic Transmission / drug effects Ubiquitin-Protein Ligases / antagonists & inhibitors Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism*
IF 8.032
Resource
C.elegans tm1516