The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development.
Cell Rep
; 19(4): 822-835, 2017 04 25.
Article
em En
| MEDLINE
| ID: mdl-28445732
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.
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Base de dados:
MEDLINE
Assunto principal:
Caenorhabditis elegans
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Proteínas de Caenorhabditis elegans
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Ubiquitina-Proteína Ligases
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Neurônios GABAérgicos
Tipo de estudo:
Etiology_studies
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Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article