title: Homeodomain protein otp and activity-dependent splicing modulate neuronal adaptation to stress.
abstract: Regulation of corticotropin-releasing hormone (CRH) activity is critical for the animal's adaptation to stressful challenges, and its dysregulation is associated with psychiatric disorders in humans. However, the molecular mechanism underlying this transcriptional response to stress is not well understood. Using various stress paradigms in mouse and zebrafish, we show that the hypothalamic transcription factor Orthopedia modulates the expression of CRH as well as the splicing factor Ataxin 2-Binding Protein-1 (A2BP1/Rbfox-1). We further show that the G protein coupled receptor PAC1, which is a known A2BP1/Rbfox-1 splicing target and an important mediator of CRH activity, is alternatively spliced in response to a stressful challenge. The generation of PAC1-hop messenger RNA isoform by alternative splicing is required for termination of CRH transcription, normal activation of the hypothalamic-pituitary-adrenal axis and adaptive anxiety-like behavior. Our study identifies an evolutionarily conserved biochemical pathway that modulates the neuronal adaptation to stress through transcriptional activation and alternative splicing.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, P.O. Box 26, Rehovot 76100, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Amir-Zilberstein
authors.forename: Janna
authors.initials: J
authors.lastname: Blechman
authors.forename: Yehezkel
authors.initials: Y
authors.lastname: Sztainberg
authors.forename: William H J
authors.initials: WH
authors.lastname: Norton
authors.forename: Adriana
authors.initials: A
authors.lastname: Reuveny
authors.forename: Nataliya
authors.initials: N
authors.lastname: Borodovsky
authors.forename: Maayan
authors.initials: M
authors.lastname: Tahor
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Bonkowsky
authors.forename: Laure
authors.initials: L
authors.lastname: Bally-Cuif
authors.forename: Alon
authors.initials: A
authors.lastname: Chen
authors.forename: Gil
authors.initials: G
authors.lastname: Levkowitz
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D001007:Anxiety / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D054641:Dual Specificity Phosphatase 2 / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D019154:Protein Splicing; D013312:Stress, Physiological / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D029961:Zebrafish Proteins; C515950:orthopedia protein, zebrafish; D054641:Dual Specificity Phosphatase 2