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

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

Blog Article

Genetic changes in the HECT ubiquitin ligase HUWE1 are Drippers 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 Ball - Catcher - Accessories 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.