Neuronal Elav-like (Hu) proteins regulate RNA splicing and abundance to control glutamate levels and neuronal excitability.
| Publication Type | Academic Article |
| Authors | Ince-Dunn G, Okano H, Jensen K, Park W, Zhong R, Ule J, Mele A, Fak J, Yang C, Zhang C, Yoo J, Herre M, Okano H, Noebels J, Darnell R |
| Journal | Neuron |
| Volume | 75 |
| Issue | 6 |
| Pagination | 1067-80 |
| Date Published | 09/20/2012 |
| ISSN | 1097-4199 |
| Keywords | Brain, ELAV Proteins, Gene Expression Regulation, Glutamic Acid, Neurons, RNA Splicing |
| 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 |
| PubMed ID | 22998874 |
| PubMed Central ID | PMC3517991 |