Neuronal Elav-like (Hu) proteins regulate RNA splicing and abundance to control glutamate levels and neuronal excitability

Neuron. 2012 Sep 20;75(6):1067-80. doi: 10.1016/j.neuron.2012.07.009.


The paraneoplastic neurologic disorders target several families of neuron-specific RNA binding proteins (RNABPs), revealing that there are unique aspects of gene expression regulation in the mammalian brain. Here, we used HITS-CLIP to determine robust binding sites targeted by the neuronal Elav-like (nElavl) RNABPs. Surprisingly, nElav protein binds preferentially to GU-rich sequences in vivo and in vitro, with secondary binding to AU-rich sequences. nElavl null mice were used to validate the consequence of these binding events in the brain, demonstrating that they bind intronic sequences in a position dependent manner to regulate alternative splicing and to 3'UTR sequences to regulate mRNA levels. These controls converge on the glutamate synthesis pathway in neurons; nElavl proteins are required to maintain neurotransmitter glutamate levels, and the lack of nElavl leads to spontaneous epileptic seizure activity. The genome-wide analysis of nElavl targets reveals that one function of neuron-specific RNABPs is to control excitation-inhibition balance in the brain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • 3' Untranslated Regions / physiology
  • Animals
  • Animals, Newborn
  • Brain / cytology*
  • Brain / metabolism
  • Computational Biology
  • Disease Models, Animal
  • ELAV Proteins / deficiency
  • ELAV Proteins / metabolism*
  • Electroencephalography
  • Epilepsy / genetics
  • Epilepsy / physiopathology
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology*
  • Glutamic Acid / metabolism*
  • Glutaminase / genetics
  • Glutaminase / metabolism
  • Mice
  • Mice, Knockout
  • Microarray Analysis
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / physiology*
  • RNA Splicing / genetics*
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism


  • 3' Untranslated Regions
  • ELAV Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Rbpms protein, mouse
  • Glutamic Acid
  • Glutaminase