Title | Neuronal Elav-like (Hu) proteins regulate RNA splicing and abundance to control glutamate levels and neuronal excitability. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Ince-Dunn G, Okano HJ, Jensen KB, Park W-Y, Zhong R, Ule J, Mele A, Fak JJ, Yang C, Zhang C, Yoo J, Herre M, Okano H, Noebels JL, Darnell RB |
Journal | Neuron |
Volume | 75 |
Issue | 6 |
Pagination | 1067-80 |
Date Published | 2012 Sep 20 |
ISSN | 1097-4199 |
Keywords | 3' Untranslated Regions, Animals, Animals, Newborn, Brain, Computational Biology, Disease Models, Animal, ELAV Proteins, Electroencephalography, Epilepsy, Gene Expression Regulation, Glutamic Acid, Glutaminase, Mice, Mice, Knockout, Microarray Analysis, Nerve Tissue Proteins, Neurons, RNA Splicing, RNA, Messenger, RNA-Binding Proteins |
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. |
DOI | 10.1016/j.neuron.2012.07.009 |
Alternate Journal | Neuron |
PubMed ID | 22998874 |
PubMed Central ID | PMC3517991 |
Grant List | R01 NS081706 / NS / NINDS NIH HHS / United States 089701 / / Wellcome Trust / United Kingdom NS29709 / NS / NINDS NIH HHS / United States K99 GM95713 / GM / NIGMS NIH HHS / United States R00 GM095713 / GM / NIGMS NIH HHS / United States K99 GM095713 / GM / NIGMS NIH HHS / United States R01 NS034389 / NS / NINDS NIH HHS / United States MC_U105185858 / / Medical Research Council / United Kingdom P30 HD024064 / HD / NICHD NIH HHS / United States UL1 RR024143 / RR / NCRR NIH HHS / United States / / Howard Hughes Medical Institute / United States R56 NS034389 / NS / NINDS NIH HHS / United States NS34389 / NS / NINDS NIH HHS / United States R01 NS029709 / NS / NINDS NIH HHS / United States HD24064 / HD / NICHD NIH HHS / United States |
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