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

  • Cell Rep. 2017 Apr 25;19(4):822-835. doi: 10.1016/j.celrep.2017.04.003.
Karla J Opperman  1 ,  Ben Mulcahy  2 ,  Andrew C Giles  1 ,  Monica G Risley  3 ,  Rayna L Birnbaum  4 ,  Erik D Tulgren  5 ,  Ken Dawson-Scully  3 ,  Mei Zhen  6 ,  Brock Grill  7
Affiliations
  • 1. Department of Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
  • 2. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • 3. Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA.
  • 4. Department of Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA; Harriet L. Wilkes Honors College, Florida Atlantic University, Jupiter, FL 33458, USA.
  • 5. Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
  • 6. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics and Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 7. Department of Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA. Electronic address: [email protected].
PMID: 28445732 DOI: 10.1016/j.celrep.2017.04.003
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.

Keywords
C. elegans; EEL-1; GABA; HUWE1; acetylcholine; intellectual disability; motor neuron; seizure; synaptic transmission; RPM-1.