The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain

• Published in: Nature genetics Vol. 43; no. 7; pp. 706 - 711
• Main Authors: Gehman, Lauren T, Stoilov, Peter, Maguire, Jamie, Damianov, Andrey, Lin, Chia-Ho, Shiue, Lily, Ares, Manuel, Mody, Istvan, Black, Douglas L
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2011; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/337/1645/1946; 692/699/375; Agriculture; Alternative Splicing; Animal Genetics and Genomics; Animals; Apoptosis; Binding proteins; Biological and medical sciences; Biomarkers - metabolism; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Brain - cytology; Brain - metabolism; Cancer Research; Cell Proliferation; Central nervous system; Electrophysiology; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation; Gene Function; Genetic aspects; Genetics of eukaryotes. Biological and molecular evolution; Homeostasis; Human Genetics; Human subjects; Immunoenzyme Techniques; Kainic Acid - toxicity; letter; Male; Methods; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons - cytology; Neurons - metabolism; Oligonucleotide Array Sequence Analysis; Physiological aspects; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA splicing; RNA Splicing Factors; RNA, Messenger - genetics; RNA-Binding Proteins - physiology; Rodents; Seizures - chemically induced; Synaptic Transmission; United States; Vertebrata; Regulation(control); Mammalia; Neuron; Splicing; Central nervous system; Encephalon
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.841

The Rbfox family of RNA binding proteins mediate alternative splicing. Douglas Black and colleagues show that targeted deletion of the mouse Rbfox1 gene in the CNS alters splice isoforms of a subset of genes and is associated with neural hyperexcitability with spontaneous and drug-induced seizures. The Rbfox family of RNA binding proteins regulates alternative splicing of many important neuronal transcripts, but its role in neuronal physiology is not clear 1 . We show here that central nervous system–specific deletion of the gene encoding Rbfox1 results in heightened susceptibility to spontaneous and kainic acid–induced seizures. Electrophysiological recording revealed a corresponding increase in neuronal excitability in the dentate gyrus of the knockout mice. Whole-transcriptome analyses identified multiple splicing changes in the Rbfox1 −/− brain with few changes in overall transcript abundance. These splicing changes alter proteins that mediate synaptic transmission and membrane excitation. Thus, Rbfox1 directs a genetic program required in the prevention of neuronal hyperexcitation and seizures. The Rbfox1 knockout mice provide a new model to study the post-transcriptional regulation of synaptic function.