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Molecular and Cellular Biology, November 2005, p. 10005-10016, Vol. 25, No. 22
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.22.10005-10016.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Homologues of the Caenorhabditis elegans Fox-1 Protein Are Neuronal Splicing Regulators in Mammals{dagger}

Jason G. Underwood,1 Paul L. Boutz,2 Joseph D. Dougherty,3 Peter Stoilov,2 and Douglas L. Black1,2,4*

Molecular Biology Institute,1 Department of Microbiology, Immunology and Molecular Genetics,2 Interdepartmental Program in Neuroscience,3 Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, California 90095-16624

Received 8 June 2005/ Returned for modification 8 July 2005/ Accepted 11 August 2005

A vertebrate homologue of the Fox-1 protein from C. elegans was recently shown to bind to the element GCAUG and to act as an inhibitor of alternative splicing patterns in muscle. The element UGCAUG is a splicing enhancer element found downstream of numerous neuron-specific exons. We show here that mouse Fox-1 (mFox-1) and another homologue, Fox-2, are both specifically expressed in neurons in addition to muscle and heart. The mammalian Fox genes are very complex transcription units that generate transcripts from multiple promoters and with multiple internal exons whose inclusion is regulated. These genes produce a large family of proteins with variable N and C termini and internal deletions. We show that the overexpression of both Fox-1 and Fox-2 isoforms specifically activates splicing of neuronally regulated exons. This splicing activation requires UGCAUG enhancer elements. Conversely, RNA interference-mediated knockdown of Fox protein expression inhibits splicing of UGCAUG-dependent exons. These experiments show that this large family of proteins regulates splicing in the nervous system. They do this through a splicing enhancer function, in addition to their apparent negative effects on splicing in vertebrate muscle and in worms.

* 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.

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

Molecular and Cellular Biology, November 2005, p. 10005-10016, Vol. 25, No. 22
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.22.10005-10016.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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