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The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development.


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.

SUBMITTER: Opperman KJ 

PROVIDER: S-EPMC5475272 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development.

Opperman Karla J KJ   Mulcahy Ben B   Giles Andrew C AC   Risley Monica G MG   Birnbaum Rayna L RL   Tulgren Erik D ED   Dawson-Scully Ken K   Zhen Mei M   Grill Brock B  

Cell reports 20170401 4


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 circu  ...[more]

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