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, ChingWen Yang, Chaolin Zhang, Jong Yoo, Margaret Herre, Hideyuki Okano, Jeffrey L. Noebels, Robert B. Darnell

Research output: Contribution to journalArticle

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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)1067-1079
Number of pages13
JournalNeuron
Volume75
Issue number6
DOIs
Publication statusPublished - 2012 Sep 20

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RNA Splicing
RNA-Binding Proteins
Glutamic Acid
Neurons
Brain
Proteins
Alternative Splicing
Gene Expression Regulation
3' Untranslated Regions
Nervous System Diseases
Neurotransmitter Agents
Epilepsy
Binding Sites
Genome
Messenger RNA

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ince-Dunn, G., Okano, H. J., Jensen, K. B., Park, W. Y., Zhong, R., Ule, J., ... Darnell, R. B. (2012). Neuronal Elav-like (Hu) Proteins Regulate RNA Splicing and Abundance to Control Glutamate Levels and Neuronal Excitability. Neuron, 75(6), 1067-1079. https://doi.org/10.1016/j.neuron.2012.07.009

Neuronal Elav-like (Hu) Proteins Regulate RNA Splicing and Abundance to Control Glutamate Levels and Neuronal Excitability. / Ince-Dunn, Gulayse; Okano, Hirotaka J.; Jensen, Kirk B.; Park, Woong Yang; Zhong, Ru; Ule, Jernej; Mele, Aldo; Fak, John J.; Yang, ChingWen; Zhang, Chaolin; Yoo, Jong; Herre, Margaret; Okano, Hideyuki; Noebels, Jeffrey L.; Darnell, Robert B.

In: Neuron, Vol. 75, No. 6, 20.09.2012, p. 1067-1079.

Research output: Contribution to journalArticle

Ince-Dunn, G, Okano, HJ, Jensen, KB, Park, WY, Zhong, R, Ule, J, Mele, A, Fak, JJ, Yang, C, Zhang, C, Yoo, J, Herre, M, Okano, H, Noebels, JL & Darnell, RB 2012, 'Neuronal Elav-like (Hu) Proteins Regulate RNA Splicing and Abundance to Control Glutamate Levels and Neuronal Excitability', Neuron, vol. 75, no. 6, pp. 1067-1079. https://doi.org/10.1016/j.neuron.2012.07.009
Ince-Dunn, Gulayse ; Okano, Hirotaka J. ; Jensen, Kirk B. ; Park, Woong Yang ; Zhong, Ru ; Ule, Jernej ; Mele, Aldo ; Fak, John J. ; Yang, ChingWen ; Zhang, Chaolin ; Yoo, Jong ; Herre, Margaret ; Okano, Hideyuki ; Noebels, Jeffrey L. ; Darnell, Robert B. / Neuronal Elav-like (Hu) Proteins Regulate RNA Splicing and Abundance to Control Glutamate Levels and Neuronal Excitability. In: Neuron. 2012 ; Vol. 75, No. 6. pp. 1067-1079.
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