Neuronal Elav-like (Hu) Proteins Regulate RNA Splicing and Abundance to Control Glutamate Levels and Neuronal Excitability

Gulayse Ince-Dunn, Hirotaka J. Okano, Kirk B. Jensen, Woong Yang Park, Ru Zhong, Jernej Ule, Aldo Mele, John J. Fak, Ching Wen Yang, Chaolin Zhang, Jong Yoo, Margaret Herre, Hideyuki Okano, Jeffrey L. Noebels, Robert B. Darnell

Research output: Contribution to journalArticlepeer-review

110 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1067-1080
Number of pages14
JournalNeuron
Volume75
Issue number6
DOIs
Publication statusPublished - 2012 Sep 20

ASJC Scopus subject areas

  • Neuroscience(all)

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