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Molecular and Cellular Biology, September 2009, p. 4757-4765, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.00608-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Developmental Control of CaV1.2 L-Type Calcium Channel Splicing by Fox Proteins ^,

Zhen Zhi Tang,¹ Sika Zheng,¹ Julia Nikolic,¹ and Douglas L. Black^1,2*

Howard Hughes Medical Institute, University of California at Los Angeles,¹ Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California 90095²

Received 9 May 2009/ Returned for modification 9 June 2009/ Accepted 17 June 2009

CaV1.2 voltage-gated calcium channels play critical roles in the control of membrane excitability, gene expression, and muscle contraction. These channels show diverse functional properties generated by alternative splicing at multiple sites within the CaV1.2 pre-mRNA. The molecular mechanisms controlling this splicing are not understood. We find that two exons in the CaV1.2 channel are controlled in part by members of the Fox family of splicing regulators. Exons 9* and 33 confer distinct electrophysiological properties on the channel and show opposite patterns of regulation during cortical development, with exon 9* progressively decreasing its inclusion in the CaV1.2 mRNA over time and exon 33 progressively increasing. Both exons contain Fox protein binding elements within their adjacent introns, and Fox protein expression is induced in cortical neurons in parallel with the changes in CaV1.2 splicing. We show that knocking down expression of Fox proteins in tissue culture cells has opposite effects on exons 9* and 33. The loss of Fox protein increases exon 9* splicing and decreases exon 33, as predicted by the positions of the Fox binding elements and by the pattern of splicing in development. Conversely, overexpression of Fox1 and Fox2 proteins represses exon 9* and enhances exon 33 splicing in the endogenous CaV1.2 mRNA. These effects of Fox proteins on exons 9* and 33 can be recapitulated in transfected minigene reporters. Both the repressive and the enhancing effects of Fox proteins are dependent on the Fox binding elements within and adjacent to the target exons, indicating that the Fox proteins are directly regulating both exons. These results demonstrate that the Fox protein family is playing a key role in tuning the properties of CaV1.2 calcium channels during neuronal development.

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* Corresponding author. Mailing address: Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095-1662. Phone: (310) 794-7644. Fax: (310) 206-8623. E-mail: dougb{at}microbio.ucla.edu

Published ahead of print on 29 June 2009.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, September 2009, p. 4757-4765, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.00608-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Lee, J.-A., Tang, Z.-Z., Black, D. L. (2009). An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons. Genes Dev. 23: 2284-2293 [Abstract] [Full Text]