1. Homeodomain protein otp and activity-dependent splicing modulate neuronal adaptation to stress
- Author
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Maayan Tahor, Gil Levkowitz, Janna Blechman, Adriana Reuveny, William H. J. Norton, Joshua L. Bonkowsky, Yehezkel Sztainberg, Nataliya Borodovsky, Liat Amir-Zilberstein, Alon Chen, Laure Bally-Cuif, Dept of Molecular Cell Biology, Weizmann Institute of Science [Rehovot, Israël], Departments of Pediatrics and Neurobiology and Anatomy, University of Utah, Institut de Neurobiologie Alfred Fessard (INAF), Centre National de la Recherche Scientifique (CNRS), and Neurobiologie et Développement (N&eD)
- Subjects
Neuroscience(all) ,Hypothalamus ,Anxiety ,Article ,Animals, Genetically Modified ,03 medical and health sciences ,Splicing factor ,0302 clinical medicine ,Mediator ,Protein splicing ,Stress, Physiological ,Animals ,Protein Splicing ,Transcription factor ,Zebrafish ,030304 developmental biology ,Genetics ,Neurons ,0303 health sciences ,biology ,Behavior, Animal ,General Neuroscience ,Alternative splicing ,Dual Specificity Phosphatase 2 ,Zebrafish Proteins ,biology.organism_classification ,Adaptation, Physiological ,Cell biology ,Ataxin ,RNA splicing ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
International audience; 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.
- Published
- 2012
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