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

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Abstract

The Rbfox family of RNA binding proteins regulates alternative splicing of many important neuronal transcripts, but its role in neuronal physiology is not clear1. 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.

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Figure 1: Rbfox1−/− brains lack Rbfox1 protein expression but possess normal morphology.
Figure 2: Rbfox1−/− brains are epileptic and hyperexcitable.
Figure 3: Rbfox1−/− brain exhibits splicing changes in transcripts affecting synaptic function and neuronal excitation.

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Acknowledgements

This work was done in collaboration with X.-D. Fu (University of California, San Diego). We thank N. Copeland (Institute of Molecular and Cell Biology, Singapore) for the recombineering vectors and bacterial strains used for generating the transgenic Rbfox1 mice and J.P. Donahue for his help with the microarray analyses. D. Geschwind, K. Martin and T. Nilsen gave us helpful comments on the manuscript. This work was supported in part by US National Institutes of Health Grants R01 GM049369 to X.D.F., R37 NS30549 and R01 MH076994 to I.M., R01 GM084317 to M.A. and D.L.B., and R01 GM49662 to D.L.B. D.L.B. is an Investigator of the Howard Hughes Medical Institute.

Author information

Project conception: D.L.B., P.S. and L.T.G. Creation of transgenic mice: P.S. Phenotypic analysis, histology, immunofluorescence and RT-PCR studies: L.T.G. Behavioral seizure analyses: J.M., L.T.G. and I.M. Electrophysiology: J.M. and I.M. iCLIP study: A.D. and C.-H.L. Microarray studies: L.S., L.T.G. and M.A. Manuscript preparation: L.T.G. and D.L.B.

Correspondence to Douglas L Black.

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