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

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.

• Authors: 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
• Journal: Neuron (Neuron) Vol. 75 Issue 6 Pg. 1067-80 (Sep 20 2012) ISSN: 1097-4199 [Electronic] United States
• PMID: 22998874 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Video-Audio Media)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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