title: 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.affiliation: Laboratory of Molecular Neuro-Oncology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
authors.forename: Gulayse
authors.initials: G
authors.lastname: Ince-Dunn
authors.forename: Hirotaka J
authors.initials: HJ
authors.lastname: Okano
authors.forename: Kirk B
authors.initials: KB
authors.lastname: Jensen
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
authors.forename: Ru
authors.initials: R
authors.lastname: Zhong
authors.forename: Jernej
authors.initials: J
authors.lastname: Ule
authors.forename: Aldo
authors.initials: A
authors.lastname: Mele
authors.forename: John J
authors.initials: JJ
authors.lastname: Fak
authors.forename: Chingwen
authors.initials: C
authors.lastname: Yang
authors.forename: Chaolin
authors.initials: C
authors.lastname: Zhang
authors.forename: Jong
authors.initials: J
authors.lastname: Yoo
authors.forename: Margaret
authors.initials: M
authors.lastname: Herre
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
authors.forename: Robert B
authors.initials: RB
authors.lastname: Darnell
mesh_terms: D020413:3' Untranslated Regions / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology* / Q000378:metabolism; D019295:Computational Biology; D004195:Disease Models, Animal; D051959:ELAV Proteins / Q000172:deficiency / Q000378:metabolism*; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D005972:Glutaminase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D051959:ELAV Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C119265:Rbpms protein, mouse; D018698:Glutamic Acid; D005972:Glutaminase