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 language | English |
|---|---|
| Pages (from-to) | 1067-1079 |
| Number of pages | 13 |
| Journal | Neuron |
| Volume | 75 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2012 Sep 20 |
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ASJC Scopus subject areas
- Neuroscience(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Neuronal Elav-like (Hu) Proteins Regulate RNA Splicing and Abundance to Control Glutamate Levels and Neuronal Excitability
AU - Ince-Dunn, Gulayse
AU - Okano, Hirotaka J.
AU - Jensen, Kirk B.
AU - Park, Woong Yang
AU - Zhong, Ru
AU - Ule, Jernej
AU - Mele, Aldo
AU - Fak, John J.
AU - Yang, ChingWen
AU - Zhang, Chaolin
AU - Yoo, Jong
AU - Herre, Margaret
AU - Okano, Hideyuki
AU - Noebels, Jeffrey L.
AU - Darnell, Robert B.
PY - 2012/9/20
Y1 - 2012/9/20
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neuron.2012.07.009
DO - 10.1016/j.neuron.2012.07.009
M3 - Article
VL - 75
SP - 1067
EP - 1079
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 6
ER -